Treatment of hepatocellular carcinoma

ABSTRACT

This disclosure provides methods for treating a hepatocellular carcinoma (e.g., unresectable HCC) with lenvatinib or a pharmaceutically acceptable salt thereof. Also encompassed by the disclosure are dosage regimens described herein of lenvatinib or a pharmaceutically acceptable salt thereof for use in treating hepatocellular carcinoma (e.g., unresectable hepatocellular carcinoma) according to any of the methods described herein. Particularly useful dosages and dose modifications upon the occurrence of an adverse event or events are also disclosed.

TECHNICAL FIELD

The present application relates generally to methods of treatinghepatocellular carcinoma.

BACKGROUND ART

Hepatocellular carcinoma (HCC) is the second leading cause of cancerdeath worldwide and is responsible for nearly 745,000 deaths each year.It usually occurs in a background of chronic liver disease, particularlyin cirrhosis, which limits the feasibility of surgical resection.Sorafenib, an oral multikinase inhibitor, extends overall survival whenused as a first-line treatment for HCC, demonstrating a medianimprovement of 2.8 months compared with placebo (10.7 months vs. 7.9months; hazard ratio [HR]: 0.69; P <0.001) despite a low response rateof 2% (Llovet, N Engl. J Med., 359:378-390, 2008).

Drug development in HCC in the past 10 years is marked by four failedphase 3 trials (of sunitinib, brivanib, linifanib, and erlotinib plussorafenib) that did not demonstrate noninferiority (Cheng, J. Clin.Oncol., 31:4067-4075, 2013; Johnson, I. Clin. Oncol., 31:36517-3524,2013; Cainap, J. Clin. Oncol., 33:172-179, 2015) or superiority (Zhu, J.Clin. Oncol., 33(6):559-66, 2015) to sorafenib in overall survival.Therefore, unresectable HCC represents a highly unmet medical need.

SUMMARY OF INVENTION

This disclosure relates, in part, to methods of treating a subject witha HCC (e.g., advanced HCC, unresectable HCC (uHCC), or advanced uHCC)with lenvatinib or a pharmaceutically acceptable salt thereof. In someembodiments, lenvatinib or a pharmaceutically acceptable salt thereof isadministered as a first-line single agent to patients with unresectableHCC. In some embodiments, the dosage of lenvatinib or a pharmaceuticallyacceptable salt thereof is modified upon the occurrence of one or moreadverse events in the treated subject.

In a first aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a dosage regimen of lenvatinib or a pharmaceuticallyacceptable salt thereof that is: (i) 12 mg/day if the body weight of thehuman subject is equal to or more than 60 kg or (ii) 8 mg/day if thebody weight of the human subject is less than 60 kg. In certainembodiments, lenvatinib or a pharmaceutically acceptable Salt thereof isadministered orally. In certain embodiments, lenvatinib or apharmaceutically acceptable salt thereof is administered once daily. Incertain embodiments, lenvatinib or a pharmaceutically acceptable saltthereof is administered orally, once daily.

In a second aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a dosage regimen of lenvatinib or apharmaceutically acceptable salt thereof that is 8 mg/day. In certainembodiments, lenvatinib or a pharmaceutically acceptable salt thereof isadministered orally. In certain embodiments, lenvatinib or apharmaceutically acceptable salt thereof is administered once daily. Incertain embodiments, lenvatinib or a pharmaceutically acceptable saltthereof is administered orally, once daily.

As used throughout this disclosure, a dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a specifieddose means that lenvatinib or a pharmaceutically acceptable salt thereofis present in the dosage regimen at the specified dose. Although such adosage regimen can contain additional components, lenvatinib or apharmaceutically acceptable salt thereof is present only at the specificdose listed. The dose of lenvatinib or a pharmaceutically acceptablesalt thereof (e.g., 12 mg, 8 mg, or 4 mg) as used throughout refers tothe dose of the free form of lenvatinib.

In a third aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma a firstdosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg. In carrying out thismethod, the human subject develops an occurrence of a first Grade 3nonhematologic toxicity during treatment with the first dosage regimen.Thereupon, the method further comprises terminating administration ofthe first dosage regimen after the occurrence of the fust Grade 3nonhematologic toxicity until the first Grade 3 nonhematologic toxicityis resolved to Grade 0-1 or baseline, and administering to the humansubject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg. In certain embodiments, the human subject develops an occurrence ofa second Grade 3 nonhematologic toxicity during treatment with thesecond dosage regimen. In such embodiments, the method further comprisesterminating administration of the second dosage regimen after theoccurrence of the second Grade 3 nonhematologic toxicity until thesecond Grade 3 nonhematologic toxicity is resolved to Grade 0-1 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 4 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg every other day if the body weight ofthe human subject is less than 60 kg. In certain embodiments, the humansubject develops an occurrence of a third Grade 3 nonhematologictoxicity during treatment with the third dosage regimen. In suchembodiments, the method further comprises terminating administration ofthe third dosage regimen after the occurrence of the third Grade 3nonhematologic toxicity until the third Grade 3 nonhematologic toxicityis resolved to Grade 0-1 or baseline, and, if the body weight of thehuman subject is equal to or more than 60 kg, administering to the humansubject a fourth dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg every otherday.

In a fourth aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma andmoderate hepatic impairment classified in Child-Pugh class B underChild-Pugh Classification a first dosage regimen comprising lenvatinibor a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. Incarrying out this method, the human subject develops an occurrence of afirst Grade 3 nonhematologic toxicity during treatment with the firstdosage regimen. Thereupon, the method further comprises terminatingadministration of the first dosage regimen after the occurrence of thefirst Grade 3 nonhematologic toxicity until the first Grade 3nonhematologic toxicity is resolved to Grade 0-1 or baseline, andadministering to the human subject a second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day. In certain embodiments, the human subject develops an occurrenceof a second Grade 3 nonhematologic toxicity during treatment with thesecond dosage regimen. In such embodiments, the method further comprisesterminating administration of the second dosage regimen after theoccurrence of the second Grade 3 nonhematologic toxicity until thesecond Grade 3 nonhematologic toxicity is resolved to Grade 0-1 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day. In certain embodiments, the human subjectdevelops an occurrence of a third Grade 3 nonhematologic toxicity duringtreatment with the third dosage regimen. In such embodiments, the methodfurther comprises terminating administration of the third dosage regimenafter the occurrence of the third Grade 3 nonhematologic toxicity.

In a fifth aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma a firstdosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg. In carrying out thismethod, the human subject develops an occurrence of a first persistentand intolerable Grade 2 or Grade 3 nonhematologic toxicity duringtreatment with the first dosage regimen. Thereupon, the method furthercomprises terminating administration of the first dosage regimen afterthe occurrence of the first persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity until the first persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity is resolved to Grade 0-1 orbaseline, and administering to the human subject a second dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 8 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg/day if the body weight of the humansubject is less than 60 kg. In certain embodiments, the human subjectdevelops an occurrence of a second persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity during treatment with the second dosageregimen. In such embodiments, the method further comprises terminatingadministration of the second dosage regimen after the occurrence of thesecond persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity until the second persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity is resolved to Grade 0-1 or baseline, andadministering to the human subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 4 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg every other day if the body weight of the humansubject is less than 60 kg. In certain embodiments, the human subjectdevelops an occurrence of a third persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity during treatment with the third dosageregimen. In such embodiments, the method further comprises terminatingadministration of the third dosage regimen after the occurrence of thethird persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity until the third persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity is resolved to Grade 0-1 or baseline, and, ifthe body weight of the human subject is equal to or more than 60 kg,administering to the human subject a fourth dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day.

In a sixth aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma andmoderate hepatic impairment classified in Child-Pugh class B underChild-Pugh Classification a first dosage regimen comprising lenvatinibor a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. Incarrying out this method, the human subject develops an occurrence of afirst persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity during treatment with the first dosage regimen. Thereupon, themethod further comprises terminating administration of the first dosageregimen after the occurrence of the first persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity until the first persistentand intolerable Grade 2 or Grade 3 nonhematologic toxicity is resolvedto Grade 0-1 or baseline, and administering to the human subject asecond dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose 4 mg/day. In certain embodiments, thehuman subject develops an occurrence of a second persistent andintolerable Grade 2 or Grade 3 nonhematologic toxicity during treatmentwith the second dosage regimen. In such embodiments, the method furthercomprises terminating administration of the second dosage regimen afterthe occurrence of the second persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity until the second persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity is resolved to Grade 0-1 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day. In certain embodiments, the human subjectdevelops an occurrence of a third persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity during treatment with the third dosageregimen. In such embodiments, the method further comprises terminatingadministration of the third dosage regimen after the occurrence of thethird persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity.

In a seventh aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma a firstdosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg. In carrying out thismethod, the human subject develops an occurrence of a first persistentand intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-lifethreatening Grade 4 laboratory abnormality during treatment with thefirst dosage regimen. Thereupon, the method further comprisesterminating administration of the first dosage regimen after theoccurrence of the first persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life threatening Grade 4 laboratoryabnormality until the first persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity or non-life threatening Grade 4 laboratoryabnormality is resolved to Grade 0-1 or baseline, and administering tothe human subject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg. In certain embodiments, the human subject develops an occurrence ofa second persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life threatening Grade 4 laboratory abnormality duringtreatment with the second dosage regimen. In such embodiments, themethod further comprises terminating administration of the second dosageregimen after the occurrence of the second persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity or non-life threatening Grade4 laboratory abnormality until the second persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity or non-life threatening Grade4 laboratory abnormality is resolved to Grade 0-1 or baseline, andadministering to the human subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 4 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg every other day if the body weight of the humansubject is less than 60 kg. In certain embodiments, the human subjectdevelops an occurrence of a third persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity or non-life threatening Grade 4laboratory abnormality during treatment with the third dosage regimen.In such embodiments, the method further comprises terminatingadministration of the third dosage regimen after the occurrence of thethird persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life threatening Grade 4 laboratory abnormality untilthe third persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life threatening Grade 4 laboratory abnormality isresolved to Grade 0-1 or baseline, and, if the body weight of the humansubject is equal to or more than 60 kg, administering to the humansubject a fourth dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg every otherday.

In an eighth aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma andmoderate hepatic impairment classified in Child-Pugh class B underChild-Pugh Classification a first dosage regimen comprising lenvatinibor a pharmaceutically acceptable salt thereof at a dose of g mg/day. Incarrying out this method, the human subject develops an occurrence of afirst persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life threatening Grade 4 laboratory abnormality duringtreatment with the first dosage regimen. Thereupon, the method furthercomprises terminating administration of the first dosage regimen afterthe occurrence of the first persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity or non-life threatening Grade 4 laboratoryabnormality until the first persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity or non-life threatening Grade 4 laboratoryabnormality is resolved to Grade 0-1 or baseline, and administering tothe human subject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day. Incertain embodiments, the human subject develops an occurrence of asecond persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life threatening Grade 4 laboratory abnormality duringtreatment with the second dosage regimen. In such embodiments, themethod further comprises terminating administration of the second dosageregimen after the occurrence of the second persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity or non-life threatening Grade4 laboratory abnormality until the second persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity or non-life threatening Grade4 laboratory abnormality is resolved to Grade 0-1 or baseline, andadministering to the human subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day. In certain embodiments, the human subject developsan occurrence of a third persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life threatening Grade 4 laboratoryabnormality during treatment with the third dosage regimen. In suchembodiments, the method further comprises terminating administration ofthe third dosage regimen after the occurrence of the third persistentand intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-lifethreatening Grade 4 laboratory abnormality.

In some embodiments of the third to eighth aspects, following or duringtreatment with the second dosage regimen, the human subject does notdevelop an occurrence of a second persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity or non-life threatening Grade 4laboratory abnormality. In such embodiments, the method furthercomprises continuing administration of the second dosage regimen to thehuman subject (i.e., not lowering the dose being given in the seconddosage regimen).

In some embodiments of the third to eighth aspects, following or duringtreatment with the third dosage regimen, the human subject does notdevelop an occurrence of a third persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity or non-life threatening Grade 4laboratory abnormality. In such embodiments, the method furthercomprises continuing administration of the third dosage regimen to thehuman subject (i.e., not lowering the dose being given in the thirddosage regimen).

In certain embodiments, the human subject develops an occurrence of aGrade 4 nonhematologic toxicity excluding a non-life-threatening Grade 4laboratory abnormality during treatment with the above dosage regimens.In such embodiments, the method further comprises terminatingadministration of the dosage regimen after the occurrence of the Grade 4nonhematologic toxicity excluding non-life-threatening Grade 4laboratory abnormality.

In a ninth aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma a firstdosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg. In carrying out thismethod, the human subject develops an occurrence of a first Grade 3hematologic toxicity or proteinuria during treatment with the firstdosage regimen. Thereupon, the method further comprises terminatingadministration of the first dosage regimen after the occurrence of thefirst Grade 3 hematologic toxicity or proteinuria until the first Grade3 hematologic toxicity or proteinuria is resolved to Grade 0-2 orbaseline, and administering to the human subject a second dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 12 mg/day if the body weight of the human subject is equalto or more than 60 kg or (ii) 8 mg/day if the body weight of the humansubject is less than 60 kg. In certain embodiments, the human subjectdevelops an occurrence of a second Grade 3 hematologic toxicity orproteinuria during treatment with the second dosage regimen. In suchembodiments, the method further comprises terminating administration ofthe second dosage regimen after the occurrence of the second Grade 3hematologic toxicity or proteinuria until the second Grade 3 hematologictoxicity or proteinuria is resolved to Grade 0-2 or baseline, andadministering to the human subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 8 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg/day if the body weight of the human subject isless than 60 kg. In certain embodiments, the human subject develops anoccurrence of a third Grade 3 hematologic toxicity or proteinuria duringtreatment with the third dosage regimen. In such embodiments, the methodfurther comprises terminating administration of the third dosage regimenafter the occurrence of the third Grade 3 hematologic toxicity orproteinuria until the third Grade 3 hematologic toxicity or proteinuriais resolved to Grade 0-2 or baseline, and administering to the humansubject a fourth dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg every other day if the body weight of the human subject isless than 60 kg. In certain embodiments, the human subject develops anoccurrence of a fourth Grade 3 hematologic toxicity or proteinuriaduring treatment with the fourth dosage regimen. In such embodiments,the method further comprises terminating administration of the fourthdosage regimen after the occurrence of the fourth Grade 3 hematologictoxicity or proteinuria until the fourth Grade 3 hematologic toxicity orproteinuria is resolved to Grade 0-2 or baseline, and, if the bodyweight of the human subject is equal to or more than 60 kg,administering to the human subject a fifth dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day.

In a tenth aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma that comprises administering to ahuman subject that has an unresectable hepatocellular carcinoma andmoderate hepatic impairment classified in Child-Pugh class B underChild-Pugh Classification a first dosage regimen comprising lenvatinibor a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. Incarrying out this method, the human subject develops an occurrence of afirst Grade 3 hematologic toxicity or proteinuria during treatment withthe first dosage regimen. Thereupon, the method further comprisesterminating administration of the first dosage regimen after theoccurrence of the first Grade 3 hematologic toxicity or proteinuriauntil the first Grade 3 hematologic toxicity or proteinuria is resolvedto Grade 0-2 or baseline, and administering to the human subject asecond dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 8 mg/day. In certain embodiments,the human subject develops an occurrence of a second Grade 3 hematologictoxicity or proteinuria during treatment with the second dosage regimen.In such embodiments, the method further comprises terminatingadministration of the second dosage regimen after the occurrence of thesecond Grade 3 hematologic toxicity or proteinuria until the secondGrade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg/day. In certain embodiments, the human subject develops anoccurrence of a third Grade 3 hematologic toxicity or proteinuria duringtreatment with the third dosage regimen. In such embodiments, the methodfurther comprises terminating administration of the third dosage regimenafter the occurrence of the third Grade 3 hematologic toxicity orproteinuria until the third Grade 3 hematologic toxicity or proteinuriais resolved to Grade 0-2 or baseline, and administering to the humansubject a fourth dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg every otherday. In certain embodiments, the human subject develops an occurrence ofa fourth Grade 3 hematologic toxicity or proteinuria during treatmentwith the fourth dosage regimen. In such embodiments, the method furthercomprises terminating administration of the fourth dosage regimen afterthe occurrence of the fourth Grade 3 hematologic toxicity orproteinuria.

In some embodiments of the ninth or tenth aspects, following or duringtreatment with the second dosage regimen, the human subject does notdevelop an occurrence of a second Grade 3 hematologic toxicity orproteinuria. In such embodiments, the method further comprisescontinuing administration of the second dosage regimen to the humansubject (i.e., not lowering the dose being given in the second dosageregimen).

In some embodiments of the ninth or tenth aspects, following or duringtreatment with the third dosage regimen, the human subject does notdevelop an occurrence of a third Grade 3 hematologic toxicity orproteinuria. In such embodiments, the method further comprisescontinuing administration of the third dosage regimen to the humansubject (i.e., not lowering the dose being given in the third dosageregimen).

In some embodiments of the ninth or tenth aspects, following or duringtreatment with the fourth dosage regimen, the human subject does notdevelop an occurrence of a fourth Grade 3 hematologic toxicity orproteinuria. In such embodiments, the method further comprisescontinuing administration of the fourth dosage regimen to the humansubject (i.e., not lowering the dose being given in the fourth dosageregimen).

In an eleventh aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma, the method comprisingadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprises lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. In carrying out this method, the human subject develops anoccurrence of a first Grade 4 hematologic toxicity during treatment withthe first dosage regimen. Thereupon, the method further comprisesterminating administration of the first dosage regimen after theoccurrence of the first Grade 4 hematologic toxicity until the firstGrade 4 hematologic toxicity is resolved to Grade 0-2 or baseline, andadministering to the human subject a second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 8 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg/day if the body weight of the human subject isless than 60 kg. In certain embodiments, the human subject develops anoccurrence of a second Grade 4 hematologic toxicity during treatmentwith the second dosage regimen. In such embodiments, the method furthercomprises terminating administration of the second dosage regimen afterthe occurrence of the second Grade 4 hematologic toxicity until thesecond Grade 4 hematologic toxicity is resolved to Grade 0-2 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 4 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg every other day if the body weight ofthe human subject is less than 60 kg. In certain embodiments, the humansubject develops an occurrence of a third Grade 4 hematologic toxicityduring treatment with the third dosage regimen. In such embodiments, themethod further comprises terminating administration of the third dosageregimen after the occurrence of the third Grade 4 hematologic toxicityuntil the third Grade 4 hematologic toxicity is resolved to Grade 0-2 orbaseline, and, if the body weight of the human subject is equal to ormore than 60 kg, administering to the human subject a fourth dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 4 mg every other day.

In a twelfth aspect, the disclosure provides a method of treatingunresectable hepatocellular carcinoma, the method comprisingadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen compriseslenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. In carrying out this method, the human subject develops anoccurrence of a first Grade 4 hematologic toxicity during treatment withthe first dosage regimen. Thereupon, the method further comprisesterminating administration of the first dosage regimen after theoccurrence of the first Grade 4 hematologic toxicity until the firstGrade 4 hematologic toxicity is resolved to Grade 0-2 or baseline, andadministering to the human subject a second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day. In certain embodiments, the human subject develops an occurrenceof a second Grade 4 hematologic toxicity during treatment with thesecond dosage regimen. In such embodiments, the method further comprisesterminating administration of the second dosage regimen after theoccurrence of the second Grade 4 hematologic toxicity until the secondGrade 4 hematologic toxicity is resolved to Grade 0-2 or baseline, andadministering to the human subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day. In certain embodiments, the human subject developsan occurrence of a third Grade 4 hematologic toxicity during treatmentwith the third dosage regimen. In such embodiments, the method furthercomprises terminating administration of the third dosage regimen afterthe occurrence of the third Grade 4 hematologic toxicity.

In a thirteenth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. If the human subject develops an occurrence of a first Grade 3hematologic toxicity or proteinuria excluding non-clinically relevantlaboratory abnormality during treatment with the first dosage regimen,then the method further comprises terminating administration of thefirst dosage regimen after the occurrence of the first Grade 3hematologic toxicity or proteinuria excluding non-clinically relevantlaboratory abnormality until the first Grade 3 hematologic toxicity orproteinuria excluding non-clinically relevant laboratory abnormality isresolved to Grade 0-2 or baseline, and administering to the humansubject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. If the human subject develops an occurrence of a first Grade 4hematologic toxicity during treatment with the first dosage regimen,then the method further comprises terminating administration of thefirst dosage regimen after the occurrence of the first Grade 4hematologic toxicity until the first Grade 4 hematologic toxicity isresolved to Grade 0-2 or baseline, and administering to the humansubject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg. If the human subject develops an occurrence of a first persistentand intolerable Grade 2 nonhematologic toxicity during treatment withthe first dosage regimen, then the method further comprises terminatingadministration of the first dosage regimen after the occurrence of thefirst persistent and intolerable Grade 2 nonhematologic toxicity, andwith or without interruption of the first dosage regimen until the firstpersistent and intolerable Grade 2 nonhematologic toxicity is resolvedto Grade 0-1 or baseline, administering to the human subject a seconddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg. If the human subjectdevelops an occurrence of a first Grade 3 nonhematologic toxicityexcluding non-clinically relevant laboratory abnormality duringtreatment with the first dosage regimen, then the method furthercomprises terminating administration of the first dosage regimen afterthe occurrence of the first Grade 3 nonhematologic toxicity excludingnon-clinically relevant laboratory abnormality until the first Grade 3nonhematologic toxicity excluding non-clinically relevant laboratoryabnormality is resolved to Grade 0-1 or baseline, and administering tothe human subject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg. If the human subject develops an occurrence of a Grade 4nonhematologic toxicity excluding nonlife-threatening laboratoryabnormality during treatment with the first dosage regimen, then themethod further comprises terminating administration of the dosageregimen after the occurrence of the Grade 4 nonhematologic toxicityexcluding nonlife-threatening laboratory abnormality.

In a fourteenth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. If the human subject develops an occurrence of a first Grade 3hematologic toxicity or proteinuria excluding non-clinically relevantlaboratory abnormality during treatment with the first dosage regimen,then the method further comprises terminating administration of thefirst dosage regimen after the occurrence of the first Grade 3hematologic toxicity or proteinuria excluding non-clinically relevantlaboratory abnormality until the first Grade 3 hematologic toxicity orproteinuria excluding non-clinically relevant laboratory abnormality isresolved to Grade 0-2 or baseline, and administering to the humansubject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 8 mg/day. If thehuman subject develops an occurrence of a first Grade 4 hematologictoxicity during treatment with the first dosage regimen, then the methodfurther comprises terminating administration of the first dosage regimenafter the occurrence of the first Grade 4 hematologic toxicity until thefirst Grade 4 hematologic toxicity is resolved to Grade 0-2 or baseline,and administering to the human subject a second dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg/day. If the human subject develops an occurrence of a firstpersistent and intolerable Grade 2 nonhematologic toxicity duringtreatment with the first dosage regimen, then the method furthercomprises terminating administration of the first dosage regimen afterthe occurrence of the first persistent and intolerable Grade 2nonhematologic toxicity, and with or without interruption of the firstdosage regimen until the first persistent and intolerable Grade 2nonhematologic toxicity is resolved to Grade 0-1 or baseline,administering to the human subject a second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day. If the human subject develops an occurrence of a first Grade 3nonhematologic toxicity excluding non-clinically relevant laboratoryabnormality during treatment with the first dosage regimen, then themethod further comprises terminating administration of the first dosageregimen after the occurrence of the first Grade 3 nonhematologictoxicity excluding non-clinically relevant laboratory abnormality untilthe first Grade 3 nonhematologic toxicity excluding non-clinicallyrelevant laboratory abnormality is resolved to Grade 0-1 or baseline,and administering to the human subject a second dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg/day. If the human subject develops an occurrence of a Grade4 nonhematologic toxicity excluding nonlife-threatening laboratoryabnormality during treatment with the first dosage regimen, then themethod further comprises terminating administration of the dosageregimen after the occurrence of the Grade 4 nonhematologic toxicityexcluding nonlife-threatening laboratory abnormality.

In some embodiments of the eleventh to fourteenth aspects, following orduring treatment with the second dosage regimen, the human subject doesnot develop an occurrence of a second Grade 4 hematologic toxicity. Insuch embodiments, the method further comprises continuing administrationof the second dosage regimen to the human subject (i.e., not loweringthe dose being given in the second dosage regimen).

In some embodiments of the eleventh to fourteenth aspects, following orduring treatment with the third dosage regimen, the human subject doesnot develop an occurrence of a third Grade 4 hematologic toxicity. Insuch embodiments, the method further comprises continuing administrationof the third dosage regimen to the human subject (i.e., not lowering thedose being given in the third dosage regimen).

In a fifteenth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a prior dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, and wherein the humansubject developed an occurrence of a Grade 3 nonhematologic toxicityduring treatment with the prior dosage regimen. In other instances, themethod comprises administering to a human subject that has anunresectable hepatocellular carcinoma a dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 4 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg every other day if the body weight of the humansubject is less than 60 kg, wherein the human subject was previouslytreated with a prior dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, and wherein the human subject developed an occurrence of a Grade 3nonhematologic toxicity during treatment with the prior dosage regimen.In yet other instances, the method comprises administering to a humansubject that has an unresectable hepatocellular carcinoma a dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 4 mg every other day, wherein the body weight ofthe human subject is equal to or more than 60 kg, wherein the humansubject was previously treated with a prior dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day, and wherein the human subject developed an occurrence of a Grade3 nonhematologic toxicity during treatment with the prior dosageregimen.

In a sixteenth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma and moderate hepatic impairment classified inChild-Pugh class B under Child-Pugh Classification a dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg/day, wherein the human subject was previously treated witha prior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 8 mg/day, and wherein the humansubject developed an occurrence of a Grade 3 nonhematologic toxicityduring treatment with the prior dosage regimen. In other instances, themethod comprises administering to a human subject that has anunresectable hepatocellular carcinoma and moderate hepatic impairmentclassified in Child-Pugh class B under Child-Pugh Classification adosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg every other day, wherein the humansubject was previously treated with a prior dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day, and wherein the human subject developed an occurrence of a Grade3 nonhematologic toxicity during treatment with the prior dosageregimen.

In a seventeenth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a prior dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, and wherein the humansubject developed an occurrence of a persistent and intolerable Grade 2or Grade 3 nonhematologic toxicity during treatment with the priordosage regimen. In other instances, the method comprises administeringto a human subject that has an unresectable hepatocellular carcinoma adosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 4 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg every other day ifthe body weight of the human subject is less than 60 kg, wherein thehuman subject was previously treated with a prior dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 8 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg/day if the body weight of the humansubject is less than 60 kg, and wherein the human subject developed anoccurrence of a persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity during treatment with the prior dosage regimen.In yet other instances, the method comprises administering to a humansubject that has an unresectable hepatocellular carcinoma a dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 4 mg every other day, wherein the body weight ofthe human subject is equal to or more than 60 kg, wherein the humansubject was previously treated with a prior dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day, and wherein the human subject developed an occurrence of apersistent and intolerable Grade 2 or Grade 3 nonhematologic toxicityduring treatment with the prior dosage regimen.

In an eighteenth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma and moderate hepatic impairment classified inChild-Pugh class B under Child-Pugh Classification a dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 ing/day, wherein the human subject was previously treated witha prior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 8 mg/day, and wherein the humansubject developed an occurrence of a persistent and intolerable Grade 2or Grade 3 nonhematologic toxicity during treatment with the priordosage regimen. In other instances, the method comprises administeringto a human subject that has an unresectable hepatocellular carcinoma andmoderate hepatic impairment classified in Child-Pugh class B underChild-Pugh Classification a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg every otherday, wherein the human subject was previously treated with a priordosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg/day, and wherein the human subjectdeveloped an occurrence of a persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity during treatment with the prior dosageregimen.

In a nineteenth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a prior dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, and wherein the humansubject developed an occurrence of a persistent and intolerable Grade 2or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4laboratory abnormality during treatment with the prior dosage regimen.In other instances, the method comprises administering to a humansubject that has an unresectable hepatocellular carcinoma a dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 4 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg every other day ifthe body weight of the human subject is less than 60 kg, wherein thehuman subject was previously treated with a prior dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 8 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg/day if the body weight of the humansubject is less than 60 kg, and wherein the human subject developed anoccurrence of a persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality during treatment with the prior dosage regimen. In certaininstances, the method comprises administering to a human subject thathas an unresectable hepatocellular carcinoma a dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the body weight of the human subject isequal to or more than 60 kg, wherein the human subject was previouslytreated with a prior dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day, andwherein the human subject developed an occurrence of a persistent andintolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality during treatmentwith the prior dosage regimen.

In a twentieth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma and moderate hepatic impairment classified inChild-Pugh class B under Child-Pugh Classification a dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg/day, wherein the human subject was previously treated witha prior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 8 mg/day, and wherein the humansubject developed an occurrence of a persistent and intolerable Grade 2or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4laboratory abnormality during treatment with the prior dosage regimen.In other instances, the method comprises administering to a humansubject that has an unresectable hepatocellular carcinoma and moderatehepatic impairment classified in Child-Pugh class B under Child-PughClassification a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg every otherday, wherein the human subject was previously treated with a priordosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg/day, and wherein the human subjectdeveloped an occurrence of a persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality during treatment with the prior dosage regimen.

In a twenty first aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a prior dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, and wherein the humansubject developed an occurrence of a Grade 3 hematologic toxicity orproteinuria during treatment with the prior dosage regimen. In someinstances, the method comprises administering to a human subject thathas an unresectable hepatocellular carcinoma a dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 8 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg/day if the body weight of the human subject isless than 60 kg, wherein the human subject was previously treated with aprior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of (i) 12 mg/day if the body weight ofthe human subject is equal to or more than 60 kg or (ii) 8 mg/day if thebody weight of the human subject is less than 60 kg, and wherein thehuman subject developed an occurrence of a Grade 3 hematologic toxicityor proteinuria during treatment with the prior dosage regimen. Incertain instances, the method comprises administering to a human subjectthat has an unresectable hepatocellular carcinoma a dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 4 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg every other day if the body weight ofthe human subject is less than 60 kg, wherein the human subject waspreviously treated with a prior dosage regimen comprising lenvatinib ora pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, and wherein the human subject developed an occurrence of a Grade 3hematologic toxicity or proteinuria during treatment with the priordosage regimen. In other instances, the method comprises administeringto a human subject that has an unresectable hepatocellular carcinoma adosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg every other day, wherein the body weightof the human subject is equal to or more than 60 kg, wherein the humansubject was previously treated with a prior dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day, and wherein the human subject developed an occurrence of a Grade3 hematologic toxicity or proteinuria during treatment with the priordosage regimen.

In a twenty second aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma and moderate hepatic impairment classified inChild-Pugh class B under Child-Pugh Classification a dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 8 mg/day, wherein the human subject was previously treated witha prior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 8 mg/day, and wherein the humansubject developed an occurrence of a Grade 3 hematologic toxicity orproteinuria during treatment with the prior dosage regimen. In otherinstances, the method comprises administering to a human subject thathas an unresectable hepatocellular carcinoma and moderate hepaticimpairment classified in Child-Pugh class B under Child-PughClassification a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day, whereinthe human subject was previously treated with a prior dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 8 mg/day, and wherein the human subject developed an occurrenceof a Grade 3 hematologic toxicity or proteinuria during treatment withthe prior dosage regimen. In yet other instances, the method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a dosage regimen comprising lenvatinibor a pharmaceutically acceptable salt thereof at a dose of 4 mg everyother day, wherein the human subject was previously treated with a priordosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg/day, and wherein the human subjectdeveloped an occurrence of a Grade 3 hematologic toxicity or proteinuriaduring treatment with the prior dosage regimen.

In a twenty third aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a prior dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, and wherein the humansubject developed an occurrence of a Grade 4 hematologic toxicity duringtreatment with the prior dosage regimen. In other instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg every other day if the body weight of the human subject isless than 60 kg, wherein the human subject was previously treated with aprior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of (i) 8 mg/day if the body weight ofthe human subject is equal to or more than 60 kg or (ii) 4 mg/day if thebody weight of the human subject is less than 60 kg, and wherein thehuman subject developed an occurrence of a Grade 4 hematologic toxicityduring treatment with the prior dosage regimen. In yet other instances,the method comprises administering to a human subject that has anunresectable hepatocellular carcinoma a dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the body weight of the human subject isequal, to or more than 60 kg, wherein the human subject was previouslytreated with a prior dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day, andwherein the human subject developed an occurrence of a Grade 4hematologic toxicity during treatment with the prior dosage regimen.

In a twenty fourth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma and moderate hepatic impairment classified inChild-Pugh class B under Child-Pugh Classification a dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg/day, wherein the human subject was previously treated witha prior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 8 ing/day, and wherein the humansubject developed an occurrence of a Grade 4 hematologic toxicity duringtreatment with the prior dosage regimen. In some instances, the methodcomprises administering to a human subject that has an unresectablehepatocellular carcinoma and moderate hepatic impairment classified inChild-Pugh class B under Child-Pugh Classification a dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day, wherein the human subject was previouslytreated with a prior dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day, andwherein the human subject developed an occurrence of a Grade 4hematologic toxicity during treatment with the prior dosage regimen.

In a twenty fifth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. The human subject develops an occurrence of a first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality during treatment with the first dosage regimen. In someinstances, the method further comprises terminating administration ofthe first dosage regimen after the occurrence of the first persistentand intolerable Grade 2 or Grade 3 adverse reaction or Grade 4laboratory abnormality until the first persistent and intolerable Grade2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality isresolved to Grade 0-1 or baseline, and administering to the humansubject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject develops an occurrence of a secondpersistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade4 laboratory abnormality during treatment with the second dosageregimen. The method further comprises terminating administration of thesecond dosage regimen after the occurrence of the second persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the second persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and administering to the human subject a thirddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 4 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg every other day ifthe body weight of the human subject is less than 60 kg, wherein thehuman subject develops an occurrence of a third persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality during treatment with the third dosage regimen. The methodfurther comprises terminating administration of the third dosage regimenafter the occurrence of the third persistent and intolerable Grade 2 orGrade 3 adverse reaction or Grade 4 laboratory abnormality until thethird persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality is resolved to Grade 0-1 or baseline,and, if the body weight of the human subject is equal to or more than 60kg, administering to the human subject a fourth dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day. In instances wherein the human subjectdevelops an occurrence of a Grade 4 adverse reaction excluding Grade 4laboratory abnormality during treatment with the first, second, third,or fourth dosage regimen, the method further comprises terminatingadministration of the dosage regimen after the occurrence of the Grade 4adverse reaction excluding Grade 4 laboratory abnormality. In the aboveaspects, Grade 3 hypertension, Grade 4 hypertension, Grade 3 cardiacdysfunction, Grade 4 cardiac dysfunction, any grade arterialthromboembolic event, Grade 3 hepatotoxicity, Grade 4 hepatotoxicity, 2g or greater proteinuria in 24 hours, Grade 3 renal failure orimpairment, Grade 4 renal failure or impairment, any Gradegastrointestinal perforation, Grade 3 fistula, Grade 4 fistula, agreater than 500 ms QT/QTc interval prolongation, a greater than 60 msincrease from baseline QT/QTc interval prolongation, and any Gradereversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3 or Grade 4 adverse reactionor Grade 4 laboratory abnormality.

In a twenty sixth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. The human subject develops an occurrence of a first persistentand intolerable Grade 2 or Grade 3 adverse reaction or Grade 4laboratory abnormality during treatment with the first dosage regimen.In some instances, the method further comprises terminatingadministration of the first dosage regimen after the occurrence of thefirst persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality until the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality is resolved to Grade 0-1 or baseline, and administering tothe human subject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day, whereinthe human subject develops an occurrence of a second persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality during treatment with the second dosage regimen. The methodfurther comprises terminating administration of the second dosageregimen after the occurrence of the second persistent and intolerableGrade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormalityuntil the second persistent and intolerable Grade 2 or Grade 3 adversereaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day, wherein the human subject develops anoccurrence of a third persistent and intolerable Grade 2 or Grade 3adverse reaction or Grade 4 laboratory abnormality during treatment withthe third dosage regimen. The method further comprises terminatingadministration of the third dosage regimen after the occurrence of thethird persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality. In instances wherein the human subjectdevelops an occurrence of a Grade 4 adverse reaction excluding Grade 4laboratory abnormality during treatment with the first, second, third,or fourth dosage regimen, the method further comprises terminitiatingadministration of the dosage regimen after the occurrence of the Grade 4adverse reaction excluding Grade 4 laboratory abnormality. In the aboveaspects, Grade 3 hypertension, Grade 4 hypertension, Grade 3 cardiacdysfunction, Grade 4 cardiac dysfunction, any grade arterialthromboembolic event, Grade 3 hepatotoxicity, Grade 4 hepatotoxicity, 2g or greater proteinuria in 24 hours, Grade 3 renal failure orimpairment, Grade 4 renal failure or impairment, any Gradegastrointestinal perforation, Grade 3 fistula, Grade 4 fistula, agreater than 500 ms QT/QTc interval prolongation, a greater than 60 msincrease from baseline QT/QTc interval prolongation, and any Gradereversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3 or Grade 4 adverse reactionor Grade 4 laboratory abnormality.

In a twenty seventh aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. In instances where the human subject develops an occurrence of afirst persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality during treatment with the first dosageregimen, the method further comprises terminating administration of thefirst dosage regimen after the occurrence of the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the first persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and administering to the human subject a seconddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg. In instances where thehuman subject develops an occurrence of a Grade 4 adverse reactionexcluding Grade 4 laboratory abnormality during treatment with the firstdosage regimen, then the method further comprises terminatingadministration of the dosage regimen after the occurrence of the Grade 4adverse reaction excluding Grade 4 laboratory abnormality. In the aboveaspects, Grade 3 hypertension, Grade 4 hypertension, Grade 3 cardiacdysfunction, Grade 4 cardiac dysfunction, any grade arterialthromboembolic event, Grade 3 hepatotoxicity, Grade 4 hepatotoxicity, 2g or greater proteinuria in 24 hours, Grade 3 renal failure orimpairment, Grade 4 renal failure or impairment, any Gradegastrointestinal perforation, Grade 3 fistula, Grade 4 fistula, agreater than 500 ms QT/QTc interval prolongation, a greater than 60 msincrease from baseline QT/QTc interval prolongation, and any Gradereversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3 or Grade 4 adverse reactionor Grade 4 laboratory abnormality.

In a twenty eighth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. In instances where the human subject develops an occurrence of afirst persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality during treatment with the first dosageregimen, the method further comprises terminating administration of thefirst dosage regimen after the occurrence of the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the first persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and administering to the human subject a seconddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg/day. In instances where the human subjectdevelops an occurrence of a Grade 4 adverse reaction excluding Grade 4laboratory abnormality during treatment with the first dosage regimen,then the method further comprises terminating administration of thedosage regimen after the occurrence of the Grade 4 adverse reactionexcluding Grade 4 laboratory abnormality. In the above aspects, Grade 3hypertension, Grade 4 hypertension, Grade 3 cardiac dysfunction, Grade 4cardiac dysfunction, any grade arterial thromboembolic event, Grade 3hepatotoxicity, Grade 4 hepatotoxicity, 2 g or greater proteinuria in 24hours, Grade 3 renal failure or impairment, Grade 4 renal failure orimpairment, any Grade gastrointestinal perforation, Grade 3 fistula,Grade 4 fistula, a greater than 500 ms QT/QTc interval prolongation, agreater than 60 ms increase from baseline QT/QTc interval prolongation,and any Grade reversible posterior leukoencephalopathy syndrome areexcluded from the persistent and intolerable Grade 2, Grade 3 or Grade 4adverse reaction or Grade 4 laboratory abnormality.

In a twenty ninth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. The human subject develops an occurrence of a first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality during treatment with the first dosage regimen. In someinstances, the method further comprises terminating administration ofthe first dosage regimen after the occurrence of the first persistentand intolerable Grade 2 or Grade 3 adverse reaction or Grade 4laboratory abnormality until the first persistent and intolerable Grade2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality isresolved to Grade 0-1 or baseline, and administering to the humansubject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject develops an occurrence of a secondpersistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade4 laboratory abnormality during treatment with the second dosageregimen. The method further comprises terminating administration of thesecond dosage regimen after the occurrence of the second persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the second persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and administering to the human subject a thirddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 4 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg every other day ifthe body weight of the human subject is less than 60 kg, wherein thehuman subject develops an occurrence of a third persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality during treatment with the third dosage regimen. The methodfurther comprises terminating administration of the third dosage regimenafter the occurrence of the third persistent and intolerable Grade 2 orGrade 3 adverse reaction or Grade 4 laboratory abnormality until thethird persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality is resolved to Grade 0-1 or baseline,and, if the body weight of the human subject is equal to or more than 60kg, administering to the human subject a fourth dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day. In instances wherein the human subjectdevelops an occurrence of a Grade 4 adverse reaction excluding Grade 4laboratory abnormality during treatment with the first, second, third,or fourth dosage regimen, the method further comprises terminatingadministration of the dosage regimen after the occurrence of the Grade 4adverse reaction excluding Grade 4 laboratory abnormality. In the aboveaspects, hypertension, cardiac dysfunction, arterial thromboembolicevent, hepatotoxicity, proteinuria, renal failure or impairment,gastrointestinal perforation, fistula, QT/QTc interval prolongation, andreversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3, or Grade 4 adverse reactionor Grade 4 laboratory abnormality.

In a thirtieth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. The human subject develops an occurrence of a first persistentand intolerable Grade 2 or Grade 3 adverse reaction or Grade 4laboratory abnormality during treatment with the first dosage regimen.In some instances, the method further comprises terminatingadministration of the first dosage regimen after the occurrence of thefirst persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality until the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality is resolved to Grade 0-1 or baseline, and administering tothe human subject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day, whereinthe human subject develops an occurrence of a second persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality during treatment with the second dosage regimen. The methodfurther comprises terminating administration of the second dosageregimen after the occurrence of the second persistent and intolerableGrade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormalityuntil the second persistent and intolerable Grade 2 or Grade 3 adversereaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day, wherein the human subject develops anoccurrence of a third persistent and intolerable Grade 2 or Grade 3adverse reaction or Grade 4 laboratory abnormality during treatment withthe third dosage regimen. The method further comprises terminatingadministration of the third dosage regimen after the occurrence of thethird persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality. In instances wherein the human subjectdevelops an occurrence of a Grade 4 adverse reaction excluding Grade 4laboratory abnormality during treatment with the first, second, third,or fourth dosage regimen, the method further comprises terminatingadministration of the dosage regimen after the occurrence of the Grade 4adverse reaction excluding Grade 4 laboratory abnormality. In the aboveaspects, hypertension, cardiac dysfunction, arterial thromboembolicevent, hepatotoxicity, proteinuria, renal failure or impairment,gastrointestinal perforation, fistula, QT/QTc interval prolongation, andreversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3, or Grade 4 adverse reactionor Grade 4 laboratory abnormality.

In a thirty first aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. In instances where the human subject develops an occurrence of afirst persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality during treatment with the first dosageregimen, the method further comprises terminating administration of thefirst dosage regimen after the occurrence of the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the first persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and administering to the human subject a seconddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg. In instances where thehuman subject develops an occurrence of a Grade 4 adverse reactionexcluding Grade 4 laboratory abnormality during treatment with the firstdosage regimen, then the method further comprises terminatingadministration of the dosage regimen after the occurrence of the Grade 4adverse reaction excluding Grade 4 laboratory abnormality. In the aboveaspects, hypertension, cardiac dysfunction, arterial thromboembolicevent, hepatotoxicity, proteinuria, renal failure or impairment,gastrointestinal perforation, fistula, QT/QTc interval prolongation, andreversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3, or Grade 4 adverse reactionor Grade 4 laboratory abnormality.

In a thirty second aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. In instances where the human subject develops an occurrence of afirst persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality during treatment with the first dosageregimen, the method further comprises terminating administration of thefirst dosage regimen after the occurrence of the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the first persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and administering to the human subject a seconddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg/day. In instances where the human subjectdevelops an occurrence of a Grade 4 adverse reaction excluding Grade 4laboratory abnormality during treatment with the first dosage regimen,then the method further comprises terminating administration of thedosage regimen after the occurrence of the Grade 4 adverse reactionexcluding Grade 4 laboratory abnormality. In the above aspects,hypertension, cardiac dysfunction, arterial thromboembolic event,hepatotoxicity, proteinuria, renal failure or impairment,gastrointestinal perforation, fistula, QT/QTc interval prolongation, andreversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3, or Grade 4 adverse reactionor Grade 4 laboratory abnormality.

In a thirty third aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. If the human subject develops an occurrence of a Grade 3hypertension during treatment with the first dosage regimen, then themethod further comprises terminating administration of the first dosageregimen after the occurrence of the Grade 3 hypertension until the Grade3 hypertension is controlled at less than or equal to Grade 2, andadministering to the human subject the second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 8 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg/day if the body weight of the human subject isless than 60 kg.

In a thirty fourth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. If the human subject develops an occurrence of a Grade 3hypertension during treatment with the first dosage regimen, then themethod further comprises terminating administration of the first dosageregimen after the occurrence of the Grade 3 hypertension until the Grade3 hypertension is controlled at less than or equal to Grade 2, andadministering to the human subject the second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day.

In a thirty fifth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. If the human subject develops an occurrence of a 2 g or greaterproteinuria in 24 hours during treatment with the first dosage regimen,then the method further comprises terminating administration of thedosage regimen after the occurrence of the 2 g or greater proteinuria in24 hours until the proteinuria is less than or equal to 2 g ofproteinuria in 24 hours and, administering to the human subject thesecond dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of (i) 8 mg/day if the body weight ofthe human subject is equal to or more than 60 kg or (ii) 4 mg/day if thebody weight of the human subject is less than 60 kg. In the aboveaspect, the human subject develops an occurrence of a nephrotic syndromeduring treatment with the first dosage regimen, and the method furthercomprises terminating administration of the dosage regimen after theoccurrence of the nephrotic syndrome.

In a thirty sixth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. If the human subject develops an occurrence of a 2 g or greaterproteinuria in 24 hours during treatment with the first dosage regimen,then the method further comprises terminating administration of thedosage regimen after the occurrence of the 2 g or greater proteinuria in24 hours until the proteinuria is less than or equal to 2 g ofproteinuria in 24 hours and, administering to the human subject thesecond dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 4 mg/day. In the above aspect, thehuman subject develops an occurrence of a nephrotic syndrome duringtreatment with the first dosage regimen, and the method furthercomprises terminating administration of the dosage regimen after theoccurrence of the nephrotic syndrome.

In a thirty seventh aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg. If the human subject develops an occurrence of a greater than 500 msQT/QTc interval prolongation or a greater than 60 ms increase frombaseline QT/QTc interval prolongation during treatment with the firstdosage regimen, then the method further comprises terminatingadministration of the dosage regimen after the occurrence of the greaterthan 500 ms QT/QTc interval prolongation or a greater than 60 msincrease from baseline QT/QTc interval prolongation until the QT/QTcinterval prolongation improves to less than or equal to 480 ms orbaseline and, administering to the human subject the second dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg.

In a thirty eighth aspect, the disclosure features a method of treatingunresectable hepatocellular carcinoma. The method comprisesadministering to a human subject that has an unresectable hepatocellularcarcinoma and moderate hepatic impairment classified in Child-Pugh classB under Child-Pugh Classification a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day. If the human subject develops an occurrence of a greater than500 ms QT/QTc interval prolongation or a greater than 60 ms increasefrom baseline QT/QTc interval prolongation during treatment with thefirst dosage regimen, then the method further comprises terminatingadministration of the dosage regimen after the occurrence of the greaterthan 500 ms QT/QTc interval prolongation or a greater than 60 msincrease from baseline QT/QTc interval prolongation until the QT/QTcinterval prolongation improves to less than or equal to 480 ms orbaseline and, administering to the human subject the second dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 4 mg/day if the body weight of the human subject isless than 60 kg.

In some embodiments of the above aspects, median overall survival is13.6 months.

In some embodiments of the above aspects, median overall survival with95% confidence interval is between 12.1 and 14.9 months.

In some embodiments of the above aspects, hazard ratio of overallsurvival compared with sorafenib at a dosage of 400 mg twice daily is0.92.

In some embodiments of the above aspects, hazard ratio of overallsurvival compared with sorafenib at a dosage of 400 mg twice daily with95% confidence interval is between 0.79 and 1.06.

In some embodiments of the above aspects, overall survival is shown inFIG. 1 (Kaplan-Meier Plot of Overall Survival).

In some embodiments of the above aspects, median progression-freesurvival is 7.4 months.

In some embodiments of the above aspects, wherein medianprogression-free survival with 95% confidence interval is between 6.9 to8.8 months.

In some embodiments of the above aspects, hazard ratio ofprogression-free survival compared with sorafenib at a dosage of 400 mgtwice daily is 0.66.

In some embodiments of the above aspects, hazard ratio ofprogression-free survival compared with sorafenib at a dosage of 400 mgtwice daily with 95% confidence interval is between 0.57 and 0.77.

In some embodiments of the above aspects, progression-free survival isshown in FIG. 2 (Kaplan-Meier Plot of Progression-Free Survival).

In some embodiments of the above aspects, median time to progression is8.9 months.

In some embodiments of the above aspects, median time to progressionwith 95% confidence interval is between 7.4 to 9.2 months.

In some embodiments of the above aspects, hazard ratio of time toprogression compared with sorafenib at a dosage of 400 mg twice daily is0.63.

In some embodiments of the above aspects, hazard ratio of time toprogression compared with sorafenib at a dosage of 400 mg twice dailywith 95% confidence interval is between 0.53 and 0.73.

In some embodiments of the above aspects, time to progression is shownin FIG. 6 (Kaplan-Meier Plot of Time to Progression).

In some embodiments of the above aspects, the objective response rate is24.1%.

In some embodiments of the above aspects, the odds ratio of objectiveresponse rate compared with sorafenib at a dosage of 400 mg twice dailyis 3.13.

In some embodiments of the above aspects, the odds ratio of objectiveresponse rate compared with sorafenib at a dosage of 400 mg twice dailywith 95% confidence interval is between 2.15 to 4.56.

In some embodiments of the above aspects, the method comprises achievingthe results shown in Table 2 or Table 10 (Efficacy Results in HCC).

In some embodiments of the above aspects, the method comprises achievingthe results shown in FIG. 15 (Quality of Life).

In some embodiments of the above aspects, the human subject consistsessentially of the subject with mild hepatic impairment classified inChild-Pugh class A under Child-Pugh Classification.

In some embodiments of the above aspects, the human subject iscategorized to stage B or stage C based on Barcelona Clinic Liver Cancer(BCLC) staging system.

In some embodiments of the above aspects, medical management of each ofthe first, second, and third persistent and intolerable Grade 2 or Grade3 nonhematologic toxicities or non-life-threatening Grade 4 laboratoryabnormality is initiated prior to terminating administration of thedosage regimen administered at the time of onset of the Grade 2 or Grade3 nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality.

In some embodiments of the above aspects, medical management of each ofthe first, second, third, and fourth Grade 3 hematologic toxicities orproteinuria is initiated prior to terminating administration of thedosage regimen administered at the time of onset of the Grade 3hematologic toxicities or proteinuria.

In some embodiments of the above aspects, medical management of each ofthe first, second, and third Grade 4 hematologic toxicities is initiatedprior to terminating administration of the dosage regimen administeredat the time of onset of the Grade 4 hematologic toxicities.

In some embodiments of the above aspects, the first persistent andintolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality is the same as thesecond and/or third persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormanality.

In some embodiments of the above aspects, the first Grade 3 hematologictoxicity or proteinuria is the same as the second and/or third Grade 3hematologic toxicity or proteinuria.

In some embodiments of the above aspects, the first Grade 4 hematologictoxicity is the same as the second and/or third Grade 4 hematologictoxicity.

In some embodiments of any of the above aspects, the Grade 3nonhematologic toxicity is selected from the group consisting of Grade 3hypertension, Grade 3 diarrhea, Grade 3 decreased appetite, Grade 3fatigue, Grade 3 arthralgia, Grade 3 myalgia, Grade 3 decreased weight,Grade 3 dysphonia, Grade 3 nausea, Grade 3 abdominal pain, Grade 3QT/QTc interval prolongation, Grade 3 hypothyroidism, Grade 3 vomiting,Grade 3 constipation, Grade 3 rash, and Grade 3 palmar-plantarerythrodysesthesia.

In some embodiments of any of the above aspects, the Grade 2 or Grade 3nonhematologic toxicity is selected from the group consisting of Grade 3hypertension, Grade 2 hypertension, Grade 3 diarrhea, Grade 2 diarrhea,Grade 3 decreased appetite, Grade 2 decreased appetite, Grade 3 fatigue,Grade 2 fatigue, Grade 3 arthralgia, Grade 2 arthralgia, Grade 3myalgia, Grade 2 myalgia, Grade 3 decreased weight, Grade 2 decreasedweight, Grade 2 alopecia, Grade 3 dysphonia, Grade 2 dysphonia, Grade 3nausea, Grade 2 nausea, Grade 3 abdominal pain, Grade 2 abdominal pain,Grade 3 QT/QTc interval prolongation, Grade 2 QT/QTc intervalprolongation, Grade 3 hypothyroidism, Grade 2 hypothyroidism, Grade 3vomiting, Grade 2 vomiting, Grade 3 constipation, Grade 2 constipation,Grade 3 rash, Grade 2 rash, Grade 3 palmar-plantar erythrodysesthesia,and Grade 2 palmar-plantar erythrodysesthesia.

In some embodiments of any of the above aspects, the Grade 4 laboratoryabnormality is selected from the group consisting of Grade 4 increase inaspartate aminotransferase, Grade 4 increase in alanineaminotransferase, Grade 4 increase in alkaline phosphatase, Grade 4hypokalernia, Grade 4 hyponatremia, Grade 4 hypoglycemia, Grade 4increase in blood bilirubin, and Grade 4 increase in gamma glutamyltransferase.

In some embodiments of any of the above aspects, the Grade 3 hematologictoxicity or proteinuria is selected from the group consisting of Grade 3proteinuria, Grade 3 thrombopenia (thrombocytopenia), Grade 3 anemia,Grade 3 decrease in white blood cell count, Grade 3 neutropenia, andGrade 3 lymphocytopenia.

In some embodiments of any of the above aspects, the Grade 4 hematologictoxicity is selected from the group consisting of Grade 4 thrombopenia(thrombocytopenia), Grade 4 anemia, Grade 4 decrease in white blood cellcount, Grade 4 neutropenia, and Grade 4 lymphocytopenia.

In some embodiments of the above aspects, lenvatinib or thepharmaceutically acceptable salt thereof is formulated as a capsule.

In some embodiments of the above aspects, lenvatinib or thepharmaceutically acceptable salt thereof is administered to the humansubject orally.

In some embodiments of the above aspects, lenvatinib or apharmaceutically acceptable salt thereof is lenvatinib mesylate.

Also encompassed by the disclosure is a dosage regimen described hereinof lenvatinib or a pharmaceutically acceptable salt thereof for use intreating hepatocellular carcinoma (e.g., unresectable hepatocellularcarcinoma) according to any of the methods described herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, the exemplary methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentapplication, including definitions, will control. The materials,methods, and examples are illustrative only and not intended to belimiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts Kaplan-Meier estimates of overall survival by treatmentgroup. CI denotes confidence interval, and HR hazard ratio.

FIG. 2 shows progression-free survival by modified Response EvaluationCriteria in Solid Tumors (mRECIST). CI denotes confidence interval, andHR hazard ratio.

FIG. 3 provides a subgroup analyses of overall survival indicatingassociated hazard ratio and 95% confidence interval. AFP denotesalpha-fetoprotein, BCLC Barcelona Clinic Liver Cancer, CI confidenceinterval, and HR hazard ratio.

FIG. 4 provides subgroup analyses of progression-free survivalindicating the associated hazard ratio and 95% confidence interval. AFPdenotes alpha-fetoprotein, BCLC Barcelona Clinic Liver Cancer, CIconfidence interval, and HR hazard ratio.

FIG. 5 provides a schematic representation of the enrollment,randomization, and treatment of the 954 patients in the phase 3 trial.

FIG. 6 is a graph providing a Kaplan-Meier Estimate of time toprogression. CI denotes confidence interval, and HR hazard ratio.

FIG. 7 provides Forest plots indicating hazard ratios for time toprogression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC,Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazardratio.

FIG. 8 provides Forest plots indicating hazard ratios for time toprogression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC,Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazardratio.

FIG. 9 provides Forest plots indicating hazard ratios for time toprogression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC,Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazardratio.

FIG. 10 provides Forest plots indicating hazard ratios for time toprogression in the subgroup analyses. AFP, alpha-fetoprotein; SCLC,Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazardratio.

FIG. 11 depicts waterfall graphs of percentage change in summed diameterof target lesions. The percentage change in lesion size is shown frombaseline to nadir.

FIG. 12 provides Forest plots indicating hazard ratios for time toprogression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC,Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazardratio.

FIG. 13 provides Forest plots indicating hazard ratios for time toprogression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC,Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazardratio.

FIG. 14 provides Forest plots indicating hazard ratios for time toprogression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC,Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazardratio.

FIG. 15 provides Forest plots of hazard ratio of time to clinicallymeaningful worsening of QLQC30 questionnaire scores (top) and HCC18questionnaire scores (bottom) comparing lenvatinib to sorafenib. *Nominal p-value; HR, hazard ratio; LCL, lower control limit; UCL, uppercontrol limit.

DESCRIPTION OF EMBODIMENTS

This disclosure provides methods of treating a human subject that has ahepatocellular carcinoma (e.g., advanced HCC, unresectable HCC, orunresectable advanced HCC). The method comprises administering to thesubject a starting dose of lenvatinib or a pharmaceutically acceptablesalt thereof. The starting dose is determined based on the body weightof the subject: 12 mg/day if the body weight of the human subject isequal to or more than 60 kg, and 8 mg/day if the body weight of thehuman subject is less than 60 kg. However, if the human subject hasmoderate hepatic impairment classified in Child-Pugh class B under theChild-Pugh Classification, then the starting dose can be 8 mg/dayregardless of the body weight of the subject. If the subject developsone or more adverse events as a result of the treatment with lenvatinibor a pharmaceutically acceptable salt thereof, the disclosure providesmodifications of the treatment regimen as well as adjusted dosingregimens (reduced doses of lenvatinib or a pharmaceutically acceptablesalt thereof). These dose modifications enable the subject to continuetreatment with lenvatinib or a pharmaceutically acceptable salt thereof.If the subject does not develop an adverse reaction as a result ofadministration of a particular dose of lenvatinib or a pharmaceuticallyacceptable salt thereof, the subject can be maintained on the samedosage regimen.

Hepatocellular Carcinoma

Primary liver cancer is the sixth most common cancer worldwide withapproximately 782,000 new cases worldwide in 2012. A total of 83% of theworld's cases occur in less-developed regions and more than 50% occur inChina alone; however, the incidence of liver cancer has been rising in anumber of low-rate areas such as Australia, the United Kingdom, and theUnited States. In all populations, males have higher rates of livercancer than do females. Liver cancer is the third most common cause ofcancer death worldwide, accounting for an estimated 746,000 cancerdeaths annually.

Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary cancerof the liver and occurs predominantly in patients with underlyingchronic liver disease, in particular cirrhosis. Major causes ofcirrhosis include hepatitis B virus (HBV), hepatitis C virus (HCV), andalcoholic liver disease. Hepatitis B is the most frequent underlyingcause of HCC, with an estimated 300 million people with chronicinfection worldwide. Chronic HBV carriers have a 5- to 15-fold increasedrisk of developing HCC compared with the general population. Chronic HCVinfection is also a major risk factor for HCC. The risk of HCC was17-fold higher in HCV-infected patients compared with HCV-negativecontrols.

To reduce mortality rates, it is important not only to prevent onset andpromote early detection of HCC in patients in whom the hepatitis viruscannot be eradicated, but also to develop effective therapeuticinterventions for patients who have already developed HCC.

For HCC, at least eight different staging systems are available. Theseinclude the Barcelona Clinic Liver Cancer (BCLC) system, the Okuda stagesystem, the TNM staging system, the JIS score, the CLIP score, the CUPIscore, the French classification, and the ER system (Pons et al., HPB,7(1):35-41, 2005). The BCLC system categorizes HCC based oncharacteristics of the tumor, liver function, performance status, andcancer-related symptoms. BCLC stage groupings include:

Very early stage. The tumor is smaller than 2 cm. There is no increasedpressure in the portal vein. Bilirubin levels are normal. Surgery isusually recommended.

Early stage. The tumor is smaller than 5 cm. Liver function varies.There may be no increased pressure in the portal vein, increased portalvein pressure and normal bilirubin levels, or increased portal veinpressure and increased bilirubin levels. People with early-stage diseasemay be candidates for a liver transplant, surgery, or radiofrequencyablation (RFA).

Intermediate stage. The tumor may be large or there may be multipletumors. Doctors usually recommend regional therapies, such astransarterial chemoembolization.

Advanced stage. The tumor has invaded the portal vein or spread to otherparts of the body, such as the lungs and bones. Targeted therapy isgenerally recommended.

Evidence-based guidelines for the diagnosis and treatment of HCC havebeen established and adopted (EI-Serag, et al., Ann. Intern. Med.,139(10):817-23, 2003; Llovet, et al., Lancet, 362(9399):1907-17, 2003).Recent technological advances for patients with early-stage HCC includesurgical resection, localized treatments such as radiofrequency ablation(RFA), percutaneous ethanol injection (PEI), cryotherapy andtransarterial chemoembolization (TACE). Treatment options for HCC aredetermined by stage of the disease. For very early stage HCC, surgicalresection is the treatment of choice in patients without cirrhosis.Among patients who have underlying cirrhosis, orthotopic livertransplantation is the treatment option associated with the lowest riskof tumor recurrence. For patients with early-stage HCC who are noteligible for surgical resection or transplantation, RFA is likely thebest alternative treatment, although PEI and cryoablation are alsoroutinely performed. Other locoregional treatment options for HCCinclude transarterial TACE, which has been shown to improve survivalamong patients with preserved liver function and unresectable HCC whosedisease is either too large or too multifocal for percutaneous ablationtechniques, as well as radioembolization, which has been used aspalliative treatment in intermediate-stage HCC. However, recurrence dueto residual tumor cells is a clinical characteristic of HCC andultimately leads to an advanced stage where surgery, RFA, and TACE areno longer appropriate.

This disclosure provides methods of treating unresectable HCC usinglenvatinib or a pharmaceutically acceptable salt thereof.

Lenvatinib

A number of kinase inhibitors have been developed as antitumor agents.For example, a group of compounds having inhibitory activity againstreceptor tyrosine kinases, such as vascular endothelial growth factorreceptor (VEGFR), are known to inhibit angiogenesis and are regarded asa new class of antitumor agents. Lenvatinib is a multi-target receptortyrosine kinase inhibitor that inhibits the kinase activities of VEGFR1(FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits otherreceptor tyrosine kinases that have been implicated in pathogenicangiogenesis, tumor growth, and cancer progression in addition to theirnormal cellular functions, including fibroblast growth factor (FGF)receptors FGFR1, FGFR2, FGFR3, and FGFR4; rearranged during transfectionreceptor (RET), KIT, and platelet-derived growth factor receptor alpha(PDGFRα). Lenvatinib also exhibits antiproliferative activity inhepatocellular carcinoma cell lines dependent on activated FGFRsignaling with a concurrent inhibition of FGF-receptor substrate 2α(FRS2α) phosphorylation.

The term “lenvatinib” refers to4-(3-chloro-4(cyclopropylaminocarbonyDaminophenoxy)-7-methoxy-6-quinollnecarboxamide. This compound is disclosed in Example 368 (see, column 270) ofU.S. Pat. Nos. 7,253,286, 7,253,286 is incorporated by reference in itsentirety herein. The term “pharmaceutically acceptable salt” is notparticularly restricted as to the type of salt. Examples of such saltsinclude, but are not limited to, inorganic acid addition salt such ashydrochloric acid salt, sulfuric acid salt, carbonic acid salt,bicarbonate salt, hydrobromic acid salt, and hydriodic acid salt;organic carboxylic acid addition salt such as acetic acid salt, maleicacid salt, lactic acid salt, tartaric acid salt, and trifluoroaceticacid salt; organic sulfonic acid addition salt such as methanesulfonicacid salt, hydroxymethanesulfonie acid salt, hydroxyethanesulfonic acidsalt, benzenesulfonic acid salt, toluenesulfonic acid salt, and taurinesalt; amine addition salt such as trimethylamine salt, triethylaminesalt, pyridine salt, procaine salt, picoline salt, dicyclohexylaminesalt, N,N′-dibenzylethylenediamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt, and phenethylbenzylamine salt; andamino acid addition salt such as arginine salt, lysine salt, serinesalt, glycine salt, aspartic acid salt, and glutamic acid salt. In oneembodiment, the pharmaceutically acceptable salt is a methanesulfonicacid salt (“mesylate”). The methanesulfonic acid salt form (i.e., themesylate) of lenvatinib is disclosed in U.S. Pat. No. 7,612,208, whichis incorporated by reference herein in its entirety. The chemical nameof lenvatinib mesylate is4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamidemethanesulfonate and it chemical structure is provided below:

Lenvatinib mesylate is also referred to asLENVIMA^((registered trademark)).

Lenvatinib mesylate is a white to pale reddish yellow powder. It isslightly soluble in water and practically insoluble in ethanol(dehydrated). The dissociation constant (pKa value) of lenvatinibmesylate is 5.05 at 25° C. The partition coefficient (log P value) is3.30.

Administration

As shown in the Examples, which describe, inter alia, the results of anopen-label phase 3 human clinical trial in subjects with unresectableHCC, lenvatinib was shown to be noninferior to sorafenib in overallsurvival (median 13.6 months with lenvatinib vs. 12.3 months withsorafenib; hazard ratio [HR]: 0.92; 95% confidence interval [CI], 0.79to 1.06). Lenvatinib prolonged progression-free survival (median 7.3 vs.3.6 months; HR: 0.64; 95% CI, 0.55 to 0.75; P<0.001) versus sorafenib.Objective response rate was 41% with lenvatinib versus 12% withsorafenib (P<0.001). In sum, lenvatinib improved progression-freesurvival, time to progression, and objective response rate versussorafenib. Thus, lenvatinib can be used for the treatment of HCC.

Lenvatinib or a pharmaceutically acceptable salt thereof may beadministered orally to a human subject in need thereof (e.g., a humansubject having advanced HCC, uHCC, or advanced uHCC) by any means thatthe health care provider deems useful.

For oral administration, the lenvatinib compound can be in the form of,e.g., a tablet, capsule, suspension, or liquid. The pharmaceuticalcomposition is preferably made in the form of a dosage unit containing aparticular amount of the active ingredient. Examples of such dosageunits are capsules, tablets, powders, granules or a suspension, withconventional additives such as lactose, mannitol, corn starch or potatostarch; with binders such as crystalline cellulose, cellulosederivatives, acacia, corn starch or gelatins; with disintegrators suchas corn starch, potato starch or sodium carboxymethyl-cellulose; andwith lubricants such as talc or magnesium stearate. The activeingredient(s) may also be administered by injection as a compositionwherein, for example, saline, dextrose or water may be used as asuitable pharmaceutically acceptable carrier.

In one embodiment, lenvatinib or a pharmaceutically acceptable saltthereof (e.g., lenvatinib mesylate) is administered to the human subjectas a capsule. The capsule can contain, lenvatinib or a pharmaceuticallyacceptable salt thereof (e.g., lenvatinib mesylate) equivalent to 1 mg,2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, or 12 mgof lenvatinib. In certain instances, the capsule contains lenvatinibmesylate equivalent to 4 mg lenvatinib. In certain instances, thecapsule contains lenvatinib mesylate equivalent to 8 mg lenvatinib. Incertain instances, the capsule contains lenvatinib mesylate equivalentto 12 mg lenvatinib. In some embodiments, these capsules also containone or more of the following inactive ingredients: calcium carbonate,mannitol, microcrystalline cellulose, hydroxypropylcellulose,hydroxypropyl cellulose (type H), and talc. In some embodiments, theshell of these capsules is a hypromellose shell and can contain one ormore of: titanium dioxide, ferric oxide yellow, and ferric oxide red.The printing ink used on the capsule may contain one or more of:shellac, black iron oxide, potassium hydroxide, and propylene glycol.

In certain embodiments, lenvatinib or a pharmaceutically acceptable saltthereof (e.g., lenvatinib mesylate) is administered to the human subjectat a dose of 12 mg once daily. This dose can be administered, e.g., asthree 4 mg capsules orally once daily. In other embodiments, lenvatinibor a pharmaceutically acceptable salt thereof (e.g., lenvatinibmesylate) is administered to the human subject at a dose of 8 mg oncedaily. This dose can be administered, e.g., as two 4 mg capsules orallyonce daily. In some embodiments, lenvatinib or a pharmaceuticallyacceptable salt thereof (e.g., lenvatinib mesylate) is administered tothe human subject at a dose of 4 mg once daily. This dose can beadministered, e.g., as one 4 mg capsule orally once daily. In someembodiments, lenvatinib or a pharmaceutically acceptable salt thereof(e.g., lenvatinib mesylate) is administered to the human subject at adose of 4 mg every other day. This dose can be administered, e.g., asone 4 mg capsule orally once every other day.

It is recommended that the subject take lenvatinib or a pharmaceuticallyacceptable salt thereof one time each day at about the same time, withor without food.

If the patient is unable to swallow the lenvatinib capsules whole, thepatient may use a cup to measure about one tablespoon of water or applejuice into a glass and place the drug capsules into the liquid withoutbreaking or crushing them. The capsules should be left in the liquid forat least 10 minutes and the contents then stirred for at least 3minutes. The patient can then drink this mixture. After drinking, thepatient should rinse the glass with a small amount of additional wateror apple juice and swallow the liquid.

In certain embodiments, lenvatinib or the pharmaceutically acceptablesalt thereof is administered to a subject that has a HCC (e.g., advancedHCC or unresectable HCC) once daily for at least 7 weeks, at least 14weeks, at least 28 weeks, at least 56 weeks, at least 84 weeks, at least112 weeks, at least 140 weeks, at least 168 weeks, or at least 196weeks.

Methods of Treatment to Control, Reduce, or Prevent Adverse Events

A major problem in treating a subject with a new therapy is thedevelopment of a treatment-emergent adverse event(s) (TEAE). Atreatment-emergent adverse event is as any adverse event not present inthe subject prior to the initiation of the treatment, or any adverseevent already present that worsens in either intensity or frequencyfollowing exposure to the treatment. In certain embodiments, the adverseevent is a persistent and intolerable adverse event.

The National Cancer Institute Common Terminology Criteria for AdverseEvents v4.0 (CTCAE, published: May 28, 2009; v4.03: Jun. 14, 2010)(incorporated by reference herein in its entirety) is a descriptiveterminology that can be utilized for adverse event reporting. The CTCAEprovides a grading (severity) scale for each adverse event term. AnAdverse Event (AE) is any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease temporally associatedwith the use of a medical treatment or procedure that may or may not beconsidered related to the medical treatment or procedure. An AE is aterm that is a unique representation of a specific event used formedical documentation and scientific analyses. An AE can be graded. TheCTCAE grade refers to the severity of the AE. The CTCAE displays Grades1 through 5 with unique clinical descriptions of severity for each AEbased on this guideline:

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnosticobservations only; intervention not indicated.

Grade 2: Moderate; minimal, local or noninvasive intervention indicated;limiting age-appropriate instrumental Activities of Daily Living (ADL).[“Instrumental ADL” refer to preparing meals, shopping for groceries orclothes, using the telephone, managing money, etc.]

Grade 3: Severe or medically significant but not immediatelylife-threatening; hospitalization or prolongation of hospitalizationindicated; disabling; limiting self-care ADL. [“Self-care ADL” refers tobathing, dressing and undressing, feeding self, using the toilet, takingmedications, and not bedridden.]

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE.

Not all Grades are appropriate for all AEs. Therefore, some AEs arelisted in the CTCAE with fewer than five options for Grade selection.

Therapy with lenvatinib or a pharmaceutically acceptable salt thereof(e.g., lenvatinib mesylate) can lead to treatment-emergent adverseevents (see Examples). In certain embodiments, the adverse eventassociated with therapy with lenvatinib or a pharmaceutically acceptablesalt thereof is a persistent and intolerable AE. In certain instances,the persistent and intolerable AE is a Grade 2 AE. In other instances,the persistent and intolerable AE is a Grade 3 AL In certainembodiments, the adverse event associated with the therapy usinglenvatinib or a pharmaceutically acceptable salt thereof is a Grade 4AE. In yet other instances, the persistent and intolerable AE is a Grade4 laboratory abnormality. In certain cases, the Grade 2 or Grade 3 AE isa nonhematological toxicity. In other cases, the Grade 3 or Grade 4 AEis a hematological toxicity. In yet other cases, the Grade 3 AE isproteinuria. The most common adverse reactions observed inlenvatinib-treated HCC subjects were, in order of decreasing frequency,hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia,and decreased weight.

Hypertension is a disorder characterized by a pathological increase inblood pressure; a repeatedly elevation in the blood pressure exceeding140 over 90 mm Hg, and is graded as follows:

Grade 1: Prehypertension (systolic BP 120-139 mm Hg or diastolic BP80-89 mm Hg)

Grade 2: Stage 1 hypertension (systolic BP 140-159 mm Hg or diastolic BP90-99 mm Hg); medical intervention indicated; recurrent or persistent(>=24 hrs); symptomatic increase by >20 mm Hg (diastolic) or to >140/90mm Hg if previously WNL; monotherapy indicated Pediatric: recurrent orpersistent (>=24 hrs) BP >ULN; monotherapy indicated

Grade 3: Stage 2 hypertension (systolic BP >=160 mm Hg or diastolicBP >=100 mm Hg); medical intervention indicated; more than one drug ormore intensive therapy than previously used indicated Pediatric: Same asadult

Grade 4: Life-threatening consequences (e.g., malignant hypertension,transient or permanent neurologic deficit, hypertensive crisis); urgentintervention indicated Pediatric: Same as adult

Grade 5: Death

Fatigue is a disorder characterized by a state of generalized weaknesswith a pronounced inability to summon sufficient energy to accomplishdaily activities and is graded as follows:

Grade 1: Fatigue relieved by rest.

Grade 2: Fatigue not relieved by rest or limiting instrumentalactivities of daily living (ADL). Instrumental ADL refer to preparingmeals, shopping for groceries or clothes, using the telephone, managingmoney, etc.

Grade 3: Fatigue not relieved by rest, limiting self-care ADL. Self-careADL refer to bathing, dressing and undressing, feeding self, using thetoilet, taking medications, and not bedridden.

Grade 4: Grade is not available.

Grade 5: Grade is not available.

Diarrhea is a disorder characterized by frequent and watery bowelmovements and is graded as follows:

Grade 1: Increase of <4 stools per day over baseline; mild increase inostomy output compared to baseline

Grade 2: Increase of 4-6 stools per day over baseline; moderate increasein ostomy output compared to baseline

Grade 3: Increase of >=7 stools per day over baseline; incontinence;hospitalization indicated; severe increase in ostomy output compared tobaseline; limiting self-care ADL

Grade 4: Life-threatening consequences; urgent intervention indicated

Grade 5: death

Decreased appetite (anorexia) is a disorder characterized by a loss ofappetite, and is graded as follows:

Grade 1: Loss of appetite without alteration in eating habits

Grade 2: Oral intake altered without significant weight loss ormalnutrition; oral nutritional supplements indicated

Grade 3: Associated with significant weight loss or malnutrition (e.g.,inadequate oral caloric and/or fluid intake); tube feeding or TPNindicated

Grade 4: Life-threatening consequences; urgent intervention indicated

Grade 5: Death

Arthralgia is a disorder characterized by a sensation of markeddiscomfort in a joint, and is graded as follows:

Grade 1: Mild pain

Grade 2: Moderate pain; limiting instrumental ADL

Grade 3: Severe pain; limiting self care ADL

Grade 4: Not available

Grade 5: Not available

Myalgia is a disorder characterized by marked discomfort sensationoriginating from a muscle or group of muscles, and is graded as follows:

Grade 1: Mild pain

Grade 2: Moderate pain; limiting instrumental ADL

Grade 3: Severe pain; limiting self care ADL

Grade 4: Not available

Grade 5: Not available

Decreased weight (weight loss) is a finding characterized by a decreasein overall body weight; for pediatrics, less than the baseline growthcurve, and is graded as follows:

Grade 1: Weight loss 5 to <10% from baseline; intervention not indicated

Grade 2: 10- <20% from baseline; nutritional support indicated

Grade 3: >=20% from baseline; tube feeding or TPN indicated

Grade 4: Not available

Grade 5: Not available

The most common serious adverse reactions (>=2%) in LENVIIVIA-treatedpatients were hepatic encephalopathy (4%), hepatic failure (3%), ascites(3%), and decreased appetite (2%).

Hepatic encephalopathy comprises hepatobiliary disorders, and is gradedas follows:

Grade 1: Asymptomatic or mild symptoms; clinical or diagnosticobservations only; intervention not indicated

Grade 2: Moderate; minimal, local or noninvasive intervention indicated;limiting age appropriate instrumental ADL

Grade 3: Severe or medically significant but not immediatelylife-threatening; hospitalization or prolongation of existinghospitalization indicated; disabling; limiting self care ADL

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death

Hepatic failure is a disorder characterized by the inability of theliver to metabolize chemicals in the body. Laboratory test resultsreveal abnormal plasma levels of ammonia, bilirubin, lacticdehydrogenase, and alkaline phosphatase. Hepatic failure is graded asfollows:

Grade 1: Not available

Grade 2: Not available

Grade 3: Asterixis or mild encephalopathy or limiting self-care ADL

Grade 4: Moderate to severe encephalopathy or coma or life-threateningconsequences

Grade 5: Death

Ascites is disorder characterized by accumulation of serous orhemorrhagic fluid in the peritoneal cavity and is graded as follows:

Grade 1: Asymptomatic or clinical or diagnostic observations only orintervention not indicated

Grade 2: Symptomatic or medical intervention indicated

Grade 3: Severe symptoms or invasive intervention indicated

Grade 4: Life-threatening consequences or urgent operative interventionindicated

Grade 5: Death

Adverse reactions led to dose reduction or interruption in about 62% ofpatients receiving LENVIMA. The most common adverse reactions (>5%)resulting in dose reduction or interruption of LENVIMA were fatigue(9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%),hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%).

Proteinuria is disorder characterized by laboratory test results thatindicate the presence of excessive protein in the urine. It ispredominantly albumin, but also globulin, and is graded as follows:

Grade 1: 1+ proteinuria; urinary protein <1.0 g/24 hrs

Grade 2: Adults: 2+ proteinuria; urinary protein 1.0-3.4 g/24 hrs;Pediatric: urine P/C (Protein/Creatinine) ratio 0.5-1.9

Grade 3: Adults: urinary protein >=3.5 g/24 hrs; Pediatric: urine P/C>1.9

Grade 4: Not Available

Grade 5: Not Available

Palmar-plantar erythrodysesthesia syndrome is a disorder characterizedby redness, marked discomfort, swelling, and tingling in the palms ofthe hands or the soles of the feet, and is graded as follows:.

Grade 1: Minimal skin changes or dermatitis (e.g., erythema, edema, orhyperkeratosis)

without pain

Grade 2: Skin changes (e.g., peeling, blisters, bleeding, edema, orhyperkeratosis) with pain; limiting instrumental ADL

Grade 3: Severe skin changes (e.g., peeling, blisters, bleeding, edema,or hyperkeratosis) with pain; limiting self-care ADL

Grade 4: Not Available

Grade 5: Not Available

Treatment discontinuation due to adverse reactions occurred in 20% ofpatients in the LENVIMA-treated group. The most common adverse reactions(>=1%) resulting in discontinuation of LENVIMA were fatigue (1%),hepatic encephalopathy (1%), hyperbilirubinemia (1%), and hepaticfailure (1%).

Hyperbilirubinemia (“Blood bilirubin increased”) is a finding based onlaboratory test results that indicate an abnormally high level ofbilirubin in the blood. Excess bilirubin is associated with jaundice.

Grade 1: >1.0 ULN-1.5×ULN (upper limit of the normal range (ULN)).

Grade 2: >1.5 ULN-3.0×ULN

Grade 3: >3.0 ULN-10.0 ×ULN

Grade 4: >10.0×ULN

Grade 5: Not Available

This disclosure provides dose modifications for therapy comprisinglenvatinib or a pharmaceutically acceptable salt thereof upon theoccurrence of a treatment-emergent adverse event(s) during the course oftreatment. In certain embodiments, a subject who has a baseline bodyweight of 60 kg or greater and who has a HCC is administered a firstdosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 12 mg/day. In other embodiments, a subject whohas a baseline body weight of less than 60 kg and who has a HCC isadministered a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 8 mg/day. In someembodiments, if a subject who has HCC and has moderate hepaticimpairment classified in Child-Pugh class B under the Child-PughClassification, then the subject is administered a first dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose 8 mg/day regardless of the body weight of the subject.

Exemplary recommendations for dose interruption, reduction, anddiscontinuation of LENVIMA for some adverse reactions are listed inTable I below.

TABLE I Dose Modifications for Exemplary Adverse Reactions AdverseReaction Severity ^(a) Dose Modifications for LENVIMA Hypertension Grade3 Withhold for Grade 3 that persists despite optimal antihypertensivetherapy. Resume at reduced dose when hypertension is controlled at lessthan or equal to Grade 2. Grade 4 Permanently discontinue forlife-threatening hypertension. Cardiac Grade 3 Withhold until improvesto Grade 0 or 1 Dysfunction or baseline. Resume at a reduced dose ordiscontinue depending on the severity and persistence of adversereaction. Grade 4 Permanently discontinue. Arterial Any GradePermanently discontinue. Thromboembolic Event Hepatotoxicity Grade 3 or4 Withhold until improves to Grade 0 to 1 or baseline. Either resume ata reduced dose or discontinue depending on severity and persistence ofhepatotoxicity. Permanently discontinue for hepatic failure. RenalFailure or Grade 3 or 4 Withhold until improves to Grade 0 to 1Impairment or baseline. Resume at a reduced dose or discontinuedepending on severity and persistence of renal impairment. Proteinuria 2g or greater Withhold until less than or equal to 2 proteinuria in gramsof proteinuria per 24 hours. 24 hours Resume at a reduced dose.Discontinue for nephrotic syndrome. Gastrointestinal Any GradePermanently discontinue. Perforation Fistula Formation Grade 3 or 4Permanently discontinue. QT Prolongation Greater than Withhold untilimproves to less than or 500 ms or equal to 480 ms or baseline. greaterthan Resume at a reduced dose. 60 ms increase from baseline ReversiblePosterior Any Grade Withhold until fully resolved. LeukoencephalopathyResume at a reduced dose or discontinue Syndrome depending on severityand persistence of neurologic symptoms. Other Adverse Persistent orWithhold until improves to Grade 0 or 1 intolerable or baseline Grade 2or 3 Resume at reduced dose. adverse reaction Grade 4 laboratoryabnormality Grade 4 Permanently discontinue. adverse reaction ^(a)National Cancer Institute Common Terminology Criteria for AdverseEvents, version 4.0.

Non-Hematologic Toxicity

In some cases, the subject may develop a Grade 1 or tolerable Grade 2adverse reaction (e.g., nonhematological toxicity) after beingadministered the first dosage regimen. In such instances, treatment ofthe subject can continue without any changes to the first dosageregimen. Following or during treatment period with the first dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 12 mg/day or 8 mg/day, if the human subject doesnot develop an intolerable Grade 2 or Grade 3 adverse reaction ornon-life-threatening Grade 4 laboratory abnormality (e.g.,nonhematological toxicity), the dosage regimen can be maintained withoutany changes to the first dosage regimen.

In some embodiments, the subject develops an intolerable Grade 2 orGrade 3 adverse reaction or non-life-threatening Grade 4 laboratoryabnormality (e.g., nonhematologic toxicity) during the period oftreatment with the first dosage regimen that is related to lenvatinibtoxicity. In certain instances, the subject develops a Grade 2 or Grade3 nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks,7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeksafter the administration of the first dosage regimen. In one embodiment,the subject develops an intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life-threatening Grade 4 laboratory abnormality within12 weeks after the administration of the first dosage regimen. Inanother embodiment, the subject develops an intolerable Grade 2 or Grade3 nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality within 16 weeks after the administration of the first dosageregimen. In certain instances, the intolerable Grade 2 or Grade 3nonhematologic toxicity is Grade 3 hypertension, Grade 2 hypertension,Grade 3 fatigue, Grade 2 fatigue, Grade 3 palmar-plantarerythrodysesthesia, Grade 2 palmar-plantar erythrodysesthesia, Grade 3diarrhea, Grade 2 diarrhea, Grade 3 decreased appetite, Grade 2decreased appetite, Grade 3 fatigue, Grade 2 fatigue, Grade 3arthralgia, Grade 2 arthralgia, Grade 3 myalgia, Grade 2 myalgia, Grade3 decreased weight, Grade 2 decreased weight, Grade 2 alopecia, Grade 3dysphonia, Grade 2 dysphonia, Grade 3 nausea, Grade 2 nausea, Grade 3abdominal pain, Grade 2 abdominal pain, Grade 3 QT/QTc intervalprolongation (Electrocardiogram QT corrected interval prolonged), Grade2 QT/QTc interval prolongation, Grade 3 hypothyroidism, Grade 2hypothyroidism, Grade 3 vomiting, Grade 2 vomiting, Grade 3constipation, Grade 2 constipation, Grade 3 rash, and Grade 2 rash. Inspecific cases, the persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity is Grade 3 hypertension, Grade 2 hypertension,Grade 3 fatigue, Grade 2 fatigue, Grade 3 diarrhea, Grade 2 diarrhea,Grade 3 decreased appetite, Grade 2 decreased appetite, Grade 3arthralgia, Grade 2 arthralgia, Grade 3 myalgia, Grade 2 myalgia, Grade3 decreased weight, or Grade 2 decreased weight. In certain instances,Grade 2 toxicities can be determined to be tolerable or intolerable byboth the subject and healthcare provider. In certain instances, theGrade 4 laboratory abnormality is Grade 4 increase in aspartateaminotransferase, Grade 4 increase in alanine aminotransferase, Grade 4increase in alkaline phosphatase, Grade 4 hypokalemia, Grade 4hyponatremia, Grade 4 hypoglycemia, Grade 4 increase in blood bilirubin,or Grade 4 increase in gamma glutamyl transferase. In the aboveembodiments, the healthcare provider can determine whether the Grade 4laboratory abnormality is life-threatening or not.

If the subject develops an intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life-threatening Grade 4 laboratory abnormality, afterbeing administered the first dosage regimen (i.e., lenvatinib or apharmaceutically acceptable salt thereof at a dose of 12 mg/day (if thepatient has a baseline body weight of greater than or equal to 60 kg) or8 mg/day (if the patient has a baseline body weight of less than 60kg)), the healthcare provider can terminate the first dosage regimen andadminister to the subject a second dosage regimen comprising lenvatinibor a pharmaceutically acceptable salt thereof at a dose of 8 mg/day (ifthe patient has a baseline body weight of greater than or equal to 60kg) or 4 mg/day (if the patient has a baseline body weight of less than60 kg). In certain instances, the second dosage regimen is administeredafter interruption of the first dosage regimen and after thenonhematologic toxicity observed after the first dosage regimen isresolved to Grade 0-1 or baseline. In some instances, the first dosageregimen is terminated only after commencement of medical management ofthe intolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality. In specificembodiments, the intolerable Grade 2 or Grade 3 adverse reaction ishypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite,or decreased weight. If the Grade 3 nonhematologic toxicity ishypertension, in one embodiment, the subject is providedantihypertensive therapy and treatment with lenvatinib or apharmaceutically acceptable salt thereof is resumed at a lower dose(e.g., 8 or 4 mg/day) when hypertension is controlled at less than orequal to Grade 1; however, therapy with lenvatinib or a pharmaceuticallyacceptable salt thereof is discontinued for life-threateninghypertension.

In some cases, even after administration of the second dosage regimen, asubject may develop an adverse reaction (e.g., nonhematologic toxicity).In certain instances, the subject develops an intolerable Grade 2 orGrade 3 nonhematologic toxicity or non-life-threatening Grade 4laboratory abnormality within I week, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12weeks after the administration of the second dosage regimen. Thenonhematologic toxicity after the second dosage regimen may be the sameas, or different from, the nonhematologic toxicity after the firstdosage regimen. The nonhematologic toxicity after the second dosageregimen may be an intolerable Grade 2 or Grade 3 nonhematologic toxicityor non-life-threatening Grade 4 laboratory abnormality. In someinstances, the nonhematologic toxicity is hypertension. In someinstances, the nonhematologic toxicity is fatigue. In some instances,the nonhematologic toxicity is arthralgia. In some instances, thenonhematologic toxicity is myalgia. In some instances, thenonhematologic toxicity is diarrhea. In some instances, thenonhematologic toxicity is decreased appetite. In some instances, thenonhematologic toxicity is decreased weight.

If the subject develops an intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life-threatening Grade 4 laboratory abnormality, afterbeing administered the second dosage regimen (i.e., lenvatinib or apharmaceutically acceptable salt thereof at a dose of 8 mg/day (if thepatient has a baseline body weight of greater than or equal to 60 kg) or4 mg/day (if the patient has a baseline body weight of less than 60kg)), the healthcare provider can terminate the second dosage regimenand administer to the subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day (if the patient has a baseline body weight of greater than orequal to 60 kg) or 4 mg every other day (if the patient has a baselinebody weight of less than 60 kg). In certain instances, the third dosageregimen is administered after interruption of the second dosage regimenand after the nonhematologic toxicity observed after the second dosageregimen is resolved to Grade 0-1 or baseline. In some instances, thesecond dosage regimen is terminated only after commencement of medicalmanagement of the intolerable Grade 2 or Grade 3 nonhematologic toxicityor non-life-threatening Grade 4 laboratory abnormality. In specificembodiments, the intolerable Grade 2 or Grade 3 nonhematologic toxicityis hypertension, fatigue, diarrhea, decreased appetite,arthralgialmyalgia, or decreased weight. If the Grade 3 nonhematologictoxicity is hypertension, in one embodiment, the subject is providedantihypertensive therapy and treatment with lenvatinib or apharmaceutically acceptable salt thereof is resumed at a lower dose(e.g., 4 mg every other day) when hypertension is controlled at lessthan or equal to Grade 1; however, therapy with lenvatinib or apharmaceutically acceptable salt thereof is discontinued forlife-threatening hypertension.

In some cases, even after administration of the third dosage regimen, asubject may develop an adverse reaction (e.g., nonhematologic toxicity).In certain instances, the subject develops an intolerable Grade 2 orGrade 3 nonhematologic toxicity or non-life-threatening Grade 4laboratory abnormality within 1 week, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12weeks after the administration of the third dosage regimen. Thenonhematologic toxicity after the third dosage regimen may be the sameas, or different from, the nonhematologic toxicity after the seconddosage regimen. The nonhematologic toxicity after the third dosageregimen may be an intolerable Grade 2 or Grade 3 nonhematologic toxicityor non-life-threatening Grade 4 laboratory abnormality. In someinstances, the nonhematologic toxicity is hypertension. In someinstances, the nonhematologic toxicity is fatigue. In some instances,the nonhematologic toxicity is arthralgia. In some instances, thenonhematologic toxicity is myalgia. In some instances, thenonhematologic toxicity is diarrhea. In some instances, thenonhematologic toxicity is decreased appetite. In some instances, thenonhematologic toxicity is decreased weight.

If the subject develops an intolerable Grade 2 or Grade 3 nonhematologictoxicity or non-life-threatening Grade 4 laboratory abnormality, afterbeing administered the third dosage regimen (i.e., lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day (if thepatient has a baseline body weight of greater than or equal to 60 kg) or4 mg every other day (if the patient has a baseline body weight of lessthan 60 kg)), the healthcare provider can terminate the third dosageregimen and administer to the subject a fourth dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day (if the patient has a baseline body weight of greaterthan or equal to 60 kg). If the patient has a baseline body weight ofless than 60 kg, in certain instances, lenvatinib therapy may bediscontinued. In certain instances, the fourth dosage regimen isadministered after interruption of the third dosage regimen and afterthe nonhematologic toxicity observed after the third dosage regimen isresolved to Grade 0-1 or baseline. In some instances, the third dosageregimen is terminated only after commencement of medical management ofthe intolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality. In specificembodiments, the persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity is hypertension, fatigue, diarrhea, decreasedappetite, arthralgia/myalgia, or decreased weight. If the Grade 3nonhematologic toxicity is hypertension, in one embodiment, the subjectis provided antihypertensive therapy and treatment with lenvatinib or apharmaceutically acceptable salt thereof is resumed at a lower dose whenhypertension is controlled at less than or equal to Grade 1; however,therapy with lenvatinib or a pharmaceutically acceptable salt thereof isdiscontinued for life-threatening hypertension.

In some embodiments, if the subject develops a Grade 4 nonhematologictoxicity excluding non-life-threatening Grade 4 laboratory abnormalityafter being administered the first, second, third, or fourth dosageregimen, the healthcare provider can terminate administration of thedosage regimen after the occurrence of the Grade 4 nonhematologictoxicity excluding non-life-threatening Grade 4 laboratory abnormality.

In some embodiments, a Grade 3 laboratory abnormality that is notclinically relevant based on a judgment of healthcare provider isexcluded from a Grade 3 nonhematologic toxicity.

In the above embodiments, a Grade 3 proteinuria is excluded from a Grade3 nonhematologic toxicity to those dosage regimens.

Grades 1 to 3 Hematologic Toxicity and/or Grades 1 to 3 Proteinuria

In some embodiments, the subject may develop a Grade 1 or Grade 2hematologic toxicity or Grade 1 or Grade 2 proteinuria during the periodof treatment with the first dosage regimen (i.e., lenvatinib or apharmaceutically acceptable salt thereof at a dose of 12 mg/day (if thepatient has a baseline body weight of greater than or equal to 60 kg) or8 mg/day (if the patient has a baseline body weight of less than 60 kg))that is related to lenvatinib toxicity. In such instances, the subjectcan continue with treatment with the first dosage regimen. However, insome cases, the subject may develop a Grade 3 adverse reaction (e.g.,hematologic toxicity or proteinuria) during the period of treatment withthe first dosage regimen that is related to lenvatinib toxicity. Incertain instances, the subject develops a Grade 3 hematologic toxicityor Grade 3 proteinuria within 1 week, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or20 weeks after the administration of the first dosage regimen. In oneembodiment, the subject develops a Grade 3 hematologic toxicity or Grade3 proteinuria within 12 weeks after the administration of the firstdosage regimen. In another embodiment, the subject develops a Grade 3hematologic toxicity or Grade 3 proteinuria within 16 weeks after theadministration of the first dosage regimen. In certain instances, theGrade 3 hematologic toxicity is Grade 3 thrombopenia (thrombocytopenia;platelet count decreased), Grade 3 anemia (hemoglobin decreased), Grade3 decrease in white blood cell count (leukocyte count decreased; whiteblood cell decreased), Grade 3 neutropenia (neutrophil count decreased),or Grade 3 lymphocytopenia (lymphocyte count decreased).

If the subject develops a Grade 3 hematologic toxicity or Grade 3proteinuria, after being administered the first dosage regimen (i.e.,lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12mg/day (if the patient has a baseline body weight of greater than orequal to 60 kg) or 8 mg/day (if the patient has a baseline body weightof less than 60 kg)), the healthcare provider can terminate the firstdosage regimen and administer to the subject a second dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 12 mg/day (if the patient has a baseline body weight of greaterthan or equal to 60 kg) or 8 mg/day (if the patient has a baseline bodyweight of less than 60 kg). In certain instances, the second dosageregimen is administered after interruption of the first dosage regimenand after the nonhematologic toxicity observed after the first dosageregimen is resolved to Grade 0-2 or baseline. In some instances, thefirst dosage regimen is terminated only after commencement of medicalmanagement of the Grade 3 hematologic toxicity. In specific embodiments,the Grade 3 hematologic toxicity is Grade 3 thrombopenia(thrombocytopenia), Grade 3 anemia, Grade 3 decrease in white blood cellcount, Grade 3 neutropenia, or Grade 3 lymphocytopenia.

In some cases, even after administration of the second dosage regimen, asubject may develop a Grade 3 hematologic toxicity or Grade 3proteinuria. In certain instances, the subject develops a Grade 3hematologic toxicity or Grade 3 proteinuria within 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, or 12 weeks after the administration of the second dosageregimen. The Grade 3 hematologic toxicity or Grade 3 proteinuria afterthe second dosage regimen may be the same as, or different from, theGrade 3 hematologic toxicity or Grade 3 proteinuria after the firstdosage regimen. The hematologic toxicity or proteinuria after the seconddosage regimen may be a Grade 3 hematologic toxicity or Grade 3proteinuria.

If the subject develops a Grade 3 hematologic toxicity or Grade 3proteinuria, after being administered the second dosage regimen (i.e.,lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12mg/day (if the patient has a baseline body weight of greater than orequal to 60 kg) or 8 mg/day (if the patient has a baseline body weightof less than 60 kg)), the healthcare provider can terminate the seconddosage regimen and administer to the subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 8 mg/day (if the patient has a baseline body weight of greaterthan or equal to 60 kg) or 4 mg/day (if the patient has a baseline bodyweight of less than 60 kg). In certain instances, the third dosageregimen is administered after interruption of the second dosage regimenand after the Grade 3 hematologic toxicity or Grade 3 proteinuriaobserved after the second dosage regimen is resolved to Grade 0-2 orbaseline. In some instances, the second dosage regimen is terminatedonly after commencement of medical management of the Grade 3 hematologictoxicity or Grade 3 proteinuria.

In some cases, even after administration of the third dosage regimen, asubject may develop a Grade 3 hematologic toxicity or Grade 3proteinuria. In certain instances, the subject develops a Grade 3hematologic toxicity or Grade 3 proteinuria within 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, or 12 weeks after the administration of the third dosageregimen. The Grade 3 hematologic toxicity or Grade 3 proteinuria afterthe third dosage regimen may be the same as, or different from, theGrade 3 hematologic toxicity or Grade 3 proteinuria after the seconddosage regimen. The Grade 3 hematologic toxicity or Grade 3 proteinuriaafter the third dosage regimen may be a Grade 3 hematologic toxicity orGrade 3 proteinuria.

If the subject develops a Grade 3 hematologic toxicity or Grade 3proteinuria, after being administered the third dosage regimen (i.e.,lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8mg/day (if the patient has a baseline body weight of greater than orequal to 60 kg) or 4 mg/day (if the patient has a baseline body weightof less than 60 kg)), the healthcare provider can terminate the thirddosage regimen and administer to the subject a fourth dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg/day (if the patient has a baseline body weight of greaterthan or equal to 60 kg) or 4 mg every other day (if the patient has abaseline body weight of less than 60 kg). In certain instances, thefourth dosage regimen is administered after interruption of the thirddosage regimen and after the Grade 3 hematologic toxicity or Grade 3proteinuria observed after the third dosage regimen is resolved to Grade0-2 or baseline. In some instances, the third dosage regimen isterminated only after commencement of medical management of the Grade 3hematologic toxicity or Grade 3 proteinuria.

In some cases, even after administration of the fourth dosage regimen, asubject may develop a Grade 3 hematologic toxicity or Grade 3proteinuria. In certain instances, the subject develops a Grade 3hematologic toxicity or Grade 3 proteinuria within 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, or 12 weeks after the administration of the third dosageregimen. The Grade 3 hematologic toxicity or Grade 3 proteinuria afterthe third dosage regimen may be the same as, or different from, theGrade 3 hematologic toxicity or Grade 3 proteinuria after the seconddosage regimen. The Grade 3 hematologic toxicity or Grade 3 proteinuriaafter the third dosage regimen may be a Grade 3 hematologic toxicity orGrade 3 proteinuria.

If the subject develops a Grade 3 hematologic toxicity or Grade 3proteinuria, after being administered the fourth dosage regimen (i.e.,lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day (if the patient has a baseline body weight of greater than orequal to 60 kg) or 4 mg every other day (if the patient has a baselinebody weight of less than 60 kg)), the healthcare provider can terminatethe fourth dosage regimen and administer to the subject a fifth dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 4 mg every other day (if the patient has a baselinebody weight of greater than or equal to 60 kg). In some cases, if thepatient has a baseline body weight of less than 60 kg, lenvatinibtreatment may be discontinued. In certain instances, the fifth dosageregimen is administered after interruption of the fourth dosage regimenand after the Grade 3 hematologic toxicity or Grade 3 proteinuriaobserved after the third dosage regimen is resolved to Grade 0-2 orbaseline. In some instances, the fourth dosage regimen is terminatedonly after commencement of medical management of the Grade 3 hematologictoxicity or Grade 3 proteinuria.

In some embodiments, a Grade 3 laboratory abnormality that is notclinically relevant based on a judgment of healthcare provider isexcluded from a Grade 3 hematologic toxicity.

Grade 4 Hematologic Toxicity

In some embodiments, the subject may develop a Grade 4 hematologictoxicity during the period of treatment with the first dosage regimen(i.e., lenvatinib or a pharmaceutically acceptable salt thereof at adose of 12 mg/day (if the patient has a baseline body weight of greaterthan or equal to 60 kg) or 8 mg/day (if the patient has a baseline bodyweight of less than 60 kg)) that is related to lenvatinib toxicity. Incertain instances, the subject develops the Grade 4 hematologic toxicitywithin 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks after theadministration of the first dosage regimen. In one embodiment, thesubject develops Grade 4 hematologic toxicity within 12 weeks after theadministration of the first dosage regimen. In another embodiment, thesubject develops the Grade 4 hematologic toxicity within 16 weeks afterthe administration of the first dosage regimen. In certain instances,the Grade 4 hematologic toxicity is Grade 4 thrombopenia(thrombocytopenia; platelet count decreased), Grade 4 anemia, Grade 4decrease in white blood cell count, Grade 4 neutropenia, or Grade 4lymphocytopenia.

If the subject develops the Grade 4 hematologic toxicity after beingadministered the first dosage regimen (i.e., lenvatinib or apharmaceutically acceptable salt thereof at a dose of 12 mg/day (if thepatient has a baseline body weight of greater than or equal to 60 kg) or8 mg/day (if the patient has a baseline body weight of less than 60kg)), the healthcare provider can terminate the first dosage regimen andadminister to the subject a second dosage regimen comprising lenvatinibor a pharmaceutically acceptable salt thereof at a dose of 8 mg/day (ifthe patient has a baseline body weight of greater than or equal to 60kg) or 4 mg/day (if the patient has a baseline body weight of less than60 kg). In certain instances, the second dosage regimen is administeredafter interruption of the first dosage regimen and after the Grade 4hematologic toxicity observed after the first dosage regimen is resolvedto Grade 0-2 or baseline. In some instances, the first dosage regimen isterminated only after commencement of medical management of the Grade 4hematologic toxicity. In specific embodiments, the Grade 4 hematologictoxicity is Grade 4 thrombopenia (thrombocytopenia), Grade 4 anemia,Grade 4 decrease in white blood cell count, Grade 4 neutropenia, orGrade 4 lymphocytopenia.

In some cases, even after administration of the second dosage regimen, asubject may develop a Grade 4 hematologic toxicity. In certaininstances, the subject develops a Grade 4 hematologic toxicity within 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of thesecond dosage regimen. The Grade 4 hematologic toxicity after the seconddosage regimen may be the same as, or different from, the Grade 4hematologic toxicity after the first dosage regimen. The hematologictoxicity after the second dosage regimen may be a persistent andintolerable Grade 4 hematologic toxicity.

If the subject develops a Grade 4 hematologic toxicity after beingadministered the second dosage regimen (i.e., lenvatinib or apharmaceutically acceptable salt thereof at a dose of 8 mg/day (if thepatient has a baseline body weight of greater than or equal to 60 kg) or4 mg/day (if the patient has a baseline body weight of less than 60kg)), the healthcare provider can terminate the second dosage regimenand administer to the subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day (if the patient has a baseline body weight of greater than orequal to 60 kg) or 4 mg every other day (if the patient has a baselinebody weight of less than 60 kg). In certain instances, the third dosageregimen is administered after interruption of the second dosage regimenand after the Grade 4 hematologic toxicity observed after the seconddosage regimen is resolved to Grade 0-2 or baseline. In some instances,the second dosage regimen is terminated only after commencement ofmedical management of the Grade 4 hematologic toxicity.

In some cases, even after administration of the third dosage regimen, asubject may develop a Grade 4 hematologic toxicity. In certaininstances, the subject develops a Grade 4 hematologic toxicity within 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of thethird dosage regimen. The Grade 4 hematologic toxicity after the thirddosage regimen may be the same as, or different from, the Grade 4hematologic toxicity after the second dosage regimen. The Grade 4hematologic toxicity after the third dosage regimen may be a persistentand intolerable Grade 4 hematologic toxicity.

If the subject develops a Grade 4 hematologic toxicity after beingadministered the third dosage regimen (i.e., lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg/day (if thepatient has a baseline body weight of greater than or equal to 60 kg) or4 mg every other day (if the patient has a baseline body weight of lessthan 60 kg)), the healthcare provider can terminate the third dosageregimen and administer to the subject a fourth dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day (if the patient has a baseline body weight of greaterthan or equal to 60 kg). If the patient has a baseline body weight ofless than 60 kg, lenvatinib therapy can, in some embodiments, bediscontinued. In certain instances, the fourth dosage regimen isadministered after interruption of the third dosage regimen and afterthe Grade 4 hematologic toxicity observed after the third dosage regimenis resolved to Grade 0-2 or baseline. In some instances, the thirddosage regimen is terminated only after commencement of medicalmanagement of the Grade 4 hematologic toxicity.

The dose modifications discussed above can be helpful in permitting asubject who develops an adverse reaction to the lenvatinib therapy(e.g., a nonhematologic toxicity, a hematologic toxicity, proteinuria,or a laboratory abnormality) to continue with and benefit from thelenvatinib therapy.

Table II below lists exemplary dose reductions for LENVIMA due toadverse reactions after administration of a first dosage regimendiscussed above.

TABLE II Exemplary Dose Modifications for LENVIMA First Dosage SecondDosage Third Dosage Indication Reduction To Reduction To Reduction ToHCC (e.g., unresectable HCC) Actual weight 8 mg 4 mg 4 mg 60 kg orgreater once daily once daily every other day Actual weight 4 mg 4 mgDiscontinue less than 60 kg once daily every other day

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted as limiting the scope of theinvention. To the extent that specific materials are mentioned, it ismerely for purposes of illustration and is not intended to limit theinvention. One skilled in the art can develop equivalent means orreactants without the exercise of inventive capacity and withoutdeparting from the scope of the invention.

EXAMPLES Example 1: Lenvatinib for Unresectable Hepatocellular Carcinoma

This Example describes the open-label phase 3 noninferiority study usinglenvatinib in unresectable HCC. In this study 478 patients wererandomized to lenvatinib (body weight >=60 kg: 12 mg/day; <60 kg: 8mg/day) and 476 to sorafenib 400 mg twice daily. The primary endpointwas overall survival. Secondary endpoints included progression-freesurvival, time to progression, objective response rate, safety, andquality of life.

Materials & Methods

Study Eligibility

Patients who were eligible for enrollment had unresectable HCC withdiagnosis confirmed histologically or cytologically or with diagnosisconfirmed clinically in accordance with the American Association for theStudy of Liver Diseases criteria. Included patients also had >=1measureable target lesion, based on modified Response EvaluationCriteria in Solid Tumors (Lencioni 2010); Barcelona Clinic Liver Cancerstage B or C categorization (Bruix Hepatology 2011); Child-Pugh class A;and Eastern Cooperative Oncology Group performance status <=1. Alleligible patients had controlled blood pressure (<=150/90 mm Hg), andadequate organ function. Patients with >=50% liver occupation, clearbile duct invasion, or portal vein invasion at the main portal vein wereexcluded. Patients also were excluded if that had received priorsystemic therapy for HCC.

Study Oversight

The study was approved by all relevant institutional review boards andwas conducted in accordance with the Declaration of Helsinki and locallaws. The trial was registered before the start of patient enrollment.All patients provided written informed consent before undergoing anystudy-specific procedures. The study was overseen by an independent datamonitoring committee.

Study Design

This multicenter phase 3 randomized open-label noninferiority study wasconducted throughout the Asia-Pacific, European, and North Americanregions. Patients were recruited from Mar. 1, 2013 through Jul. 30,2016. Randomization was stratified according to region (Asia-Pacific orWestern regions), macroscopic portal vein invasion and/or extrahepaticspread (yes or no), Eastern Cooperative Oncology Group performancestatus (0 or 1), and body weight (<60 kg or >=60 kg). Withinstratification factors, patients were randomly assigned (1:1) to receiveoral lenvatinib at a dosage of 12 mg per day (for body weight >=60 kg)or 8 mg per day (for body weight <60 kg) or sorafenib at a dosage of 400mg twice daily in 28-day cycles. Dosage interruptions and reductions forlenvatinib-related toxicities (to 8 and 4 mg per day, or 4 mg everyother day) were permitted. Modifications to sorafenib dosage wereimplemented according to prescribing information in each region.

Endpoints and Assessments

The primary endpoint was overall survival. Secondary endpoints includedprogression-free survival, time to progression, objective response rate,and quality of life as measurements including use of EORTC QLQ-C30(Cocks, J, Clin. Oncol., 29:89-96, 2011, Giesinger, J., Clin.Epidemiol., 69:79-88, 2016) and HCC-specific EORTC QLQ-HCC18 (Chie,Hepatology, 55(4):1122-9, 2012) health questionnaires.

Tumors were evaluated in accordance with mRECIST (Lencioni R., SeminLiver Dis., 30(1):52-60, 2010); RECIST 1.1 was applied for nonhepaticlesions (Eisenhauer, Eur J Cancer, 45(2):228-47, 2009). The liver wasexamined with computed tomography or magnetic resonance imaging wasperformed using a triphasic scanning technique. Assessments wereperformed every 8 weeks until disease progression. Quality of lifequestionnaires were administered at baseline, on day 1 of eachsubsequent treatment cycle, and at the off-treatment visit.

Safety assessments included recording of vital signs, hematologic andbiochemical laboratory testing, urinalysis, and electrocardiography.Adverse events were graded according to the National Cancer InstituteCommon Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0,NCI 2013).

Statistical Analysis

The primary endpoint of overall survival was first tested fornoninferiority then for superiority. The required number of events forthe primary analysis was 700 deaths, based on the full analysis set. TheHR and its 95% confidence interval (Cl) were estimated from a Coxproportional hazard model with treatment group as a factor and with theanalysis stratified according to the same factors applied forrandomization. The noninferiority margin was set at 1.08 based onprevious phase 3 trials of sorafenib (Llovet NUM 2008, Cheng LancetOncol 2009).

A fixed-sequence procedure was followed to control the overall type Ierror rate of analyses for both the primary and secondary efficacyendpoints at α=0.05 (2-sided). After noninferiority was declared,secondary efficacy endpoints were tested. Differences inprogression-free survival and time to progression were evaluated using astratified log-rank test with randomization stratification factors, withthe associated HR and its 95% CI. A difference in the objective responserate was evaluated using the Cochran-Mantel-Haenszel chi-square testwith randomized stratification factors as strata, with associated oddsratio and its 95% CI. To assess futility, 2 interim analyses (at 30% and70% of the target number of events) were performed using Bayesianpredictive probability in a noninferiority design by the independentdata monitoring committee.

Patients

A total of 954 patients from 20 countries were randomly assigned toreceive lenvatinib (478 patients) or sorafenib (476 patients) (FIG. 5).The efficacy analysis followed the intent to treat principle. Onlypatients who received treatment (lenvatinib, 476 patients; sorafenib,475 patients) were included in the safety analysis. Patientcharacteristics at baseline were well balanced between treatment groups,with the exception of baseline hepatitis C and alpha-fetoprotein level(Table 1).

TABLE 1 Demographic and Disease Characteristics at Baseline. LenvatinibSorafenib Total (N = 478) (N = 476) (N = 954) Age - yr Mean 61.3 61.261.3 Standard Deviation 11.7 12.0 11.8 Age group (yr) - no. (%) <65 270(56.5) 283 (59.5) 553 (58.0) ≥65 to <75 150 (31.4) 126 (26.5) 276 (28.9)≥75 58 (12.1) 67 (14.1) 125 (13.1) Sex - no. (%) Male 405 (84.7) 401(84.2) 806 (84.5) Female 73 (15.3) 75 (15.8) 148 (15.5) Region - no. (%)Western 157 (32.8) 157 (33.0) 314 (32.9) Asia-Pacific 321 (67.2) 319(67.0) 640 (67.1) Race - no. (%) White 135 (28.2) 141 (29.6) 276 (28.9)Asian 334 (69.9) 326 (68.5) 660 (69.2) Body weight (kg) - no. (%) <60153 (32.0) 146 (30.7) 299 (31.3) ≥60 325 (68.0) 330 (69.3) 655 (68.7)ECOG performance status - no. (%) 0 304 (63.6) 301 (63.2) 605 (63.4) 1174 (36.4) 175 (36.8) 349 (36.6) Child-Pugh class - no. (%) CP-A 475(99.4) 471 (98.9) 946 (99.2) CP-B 3 (0.6) 5 (1.1) 8 (0.8) Macroscopicportal vein invasion - no. (%) Yes 109 (22.8) 90 (18.9) 199 (20.9) No369 (77.2) 386 (81.1) 755 (79.1) Extrahepatic spread - no. (%) Yes 291(60.9) 295 (62.0) 586 (61.4) No 187 (39.1) 181 (38.0) 368 (38.6)Macroscopic portal vein invasion, extrahepatic spread, or both - no. (%)Yes 329 (68.8) 336 (70.6) 665 (69.7) No 149 (31.2) 140 (29.4) 289 (30.3)Underlying cirrhosis based on medical history - no. (%) Yes 243 (50.8)231 (48.5) 474 (49.7) No 235 (49.2) 245 (51.5) 480 (50.3) BarcelonaClinic Liver Cancer stage - no. (%) B (intermediate stage) 104 (21.8) 92(19.3) 196 (20.5) C (advanced stage) 374 (78.2) 384 (80.7) 758 (79.5)Involved disease sites - no. (%) Liver 441 (92.3) 430 (90.3) 871 (91.3)Lung 163 (34.1) 144 (30.3) 307 (32.2) Involved disease sites perpatient - no. (%) 1 207 (43.3) 207 (43.5) 414 (43.4) 2 167 (34.9) 183(38.4) 350 (36.7) ≥3 103 (21.5) 86 (18.1) 189 (19.8) Etiology of chronicliver disease - no. (%) Hepatitis B 251 (52.5) 228 (47.9) 479 (50.2)Hepatitis C 91 (19.0) 126 (26.5) 217 (22.7) Alcohol 36 (7.5) 21 (4.4) 57(6.0) Other 38 (7.9) 32 (6.7) 70 (7.3) Unknown 62 (13.0) 69 (14.5) 131(13.7) Baseline alpha- fetoprotein level - ng/mL No. of patients 471 463934 Mean 17507.7 16678.5 17096.5 Standard deviation 105137.4 94789.5100088.8 Median 133.1 71.2 89.0 Range 0-1567470 0-1446396 0-1567470Baseline alpha- fetoprotein level group (ng/mL) - no. (%) <200 255(53.3) 286 (60.1) 541 (56.7) ≥200 222 (46.4) 187 (39.3) 409 (42.9)Missing 1 (0.2) 3 (0.6) 4 (0.4) Concomitant 163 (34.1) 149 (31.3) 312(32.7) systemic antiviral therapy for Hepatitis B or C - no. (%) Priortherapy - no. (%) Prior anticancer 327 (68.4) 344 (72.3) 671 (70.3)procedures Radiotherapy 49 (10.3) 60 (12.6) 109 (11.4) ECOG, EasternCooperative Oncology Group. At the time of data cutoff (Nov. 13, 2016)the median duration of follow-up was 27.7 months in the lenvatinib groupand 27.2 months in the sorafenib group.

Efficacy

Lenvatinib demonstrated noninferiority in overall survival compared withsorafenib. The median overall survival was 13.6 months (95% CI, 12.1 to14.9) with lenvatinib compared with 12.3 months (95% CI, 10.4 to 13.9)with sorafenib (HR: 0.92; 95% CI, 0.79 to 1.06) (FIG. 1). Median overallsurvival for the lenvatinib treatment arm was numerically longer in allthe prespecified strata, with the exception of the patients from Westernregions subgroup; and was the same in patients who had neithermacroscopic portal vein invasion nor extrahepatic spread (FIG. 3).Patients with baseline alphafetoprotein <200 ng/mL had longer overallsurvival than those with alpha-fetoprotein >=200 ng/mL (FIG. 3). The HRwas <1 favoring lenvatinib in both alpha-fetoprotein subgroups, butthere were more patients with baseline alpha-fetoprotein level <200ng/mL in the sorafenib arm (60.1%) compared with the lenvatinib arm(53.3%, Table 1).

Lenvatinib demonstrated a statistically significant improvement comparedto sorafenib in all secondary efficacy endpoints as determined by tumorassessment based on mRECIST. Median progression-free survival for]envatinib was 7.4 months (95% CI, 6.9 to 8.8 months) compared with 3.7months (95% CI, 3.6 to 4.6 months) with sorafenib (HR: 0.66; 95% CI,0.57 to 0.77; P<0.001) (FIG. 2). In addition, progression-free survivalin each of the prespecified subgroups was longer with lenvatinibcompared with sorafenib (FIG. 4). The median time to progression was 8.9months (95% CI, 7.4 to 9.2 months) for patients in the lenvatinib groupcompared with 3.7 months (95% CI, 3.6 to 5.4 months) for patients in thesorafenib group (HR: 0.63; 95% CI, 0.53 to 0.73; P<0.001) (Table 2 andFIG. 6).

TABLE 2 Efficacy Measures. Lenvatinib Sorafenib Hazard Ratio Outcome (N= 478) (N = 476) (95% CI) Median (95% CI) 13.6  12.3  0.92 overallsurvival - mo (12.1-14.9) (10.4-13.9) (0.79-1.06) Median (95% CI) 7.43.7 0.66 progression-free (6.9-8.8) (3.6-4.6) (0.57-0.77) survival - moP < 0.001 Median (95% CI) 8.9 3.7 0.63 time to progression - (7.4-9.2)(3.6-5.4) (0.53-0.73) mo P < 0.001 Objective response 115 (24.1) 44(9.2)  3.13† rate*- no. (%) 95% CI 20.2-27.9  6.6-11.8 (2.15-4.56)Complete response  6 (1.3)  2 (0.4) P < 0.001 Partial response 109(22.8) 42 (8.8) Stable disease 246 (51.5) 244 (51.3) Durable stabledisease 167 (34.9) 139 (29.2) lasting ≥23 wk Progressive disease  71(14.9) 147 (30.9) Unknown/not evaluable 46 (9.6) 41 (8.6) Diseasecontrol rate‡ - no. (%) 95% CI  361 (75.5]) 288 (60.5) 71.7-79.456.1-64.9 *The objective response rate was determined according tomRECIST (modified Response Evaluation Criteria in Solid Tumors). †Oddsratio. ‡The disease control rate is computed as follows: completeresponse + partial response + stable disease. CI, confidence interval.

Median time to progression with lenvatinib treatment was alsonumerically longer in each of the prespecified strata compared withsorafenib (FIGS. 7-10). Lenvatinib showed an objective response rate of24.1% versus 9.2% for sorafenib (odds ratio, 3.13; 95% CI, 2.15 to 4.56;P<0.001) (Table 2 and FIG. 11). The odds ratio favored lenvatinib in allprespecified subgroups, with the exception of the alcohol etiologysubgroup (FIGS. 12-14). Analysis for overall survival withstratification factors and other subgroups supports the robustness ofthe noninferiority result (Table 3).

TABLE 3 Overall Survival with Stratification Factors Adjusted byBaseline Characteristics. Hazard Ratio for (Lenvatinib/Sorafenib)Baseline Characteristics (95% CI) Overall 0.916 (0.789-1.064) Age (<65,≥65 to <75, ≥75 yr) 0.919 (0.791-1.067) Sex (male, female) 0.916(0.789-1.064) Region (Asia-Pacific, Western) 0.915 (0.789-1.062)Macroscopic portal vein invasion (yes, no) 0.910 (0.784-1.057)Extrahepatic spread (yes, no) 0.915 (0.788-1.062) Macroscopic portalvein invasion, extrahepatic 0.908 (0.783-1.054) spread or both (yes, no)ECOG-PS (0, ≥1) 0.923 (0.795-1.071) Body weight (<60 kg, ≥60 kg) 0.923(0.796-1.071) AFP at baseline (<200 ng/mL, ≥200 ng/mL) 0.856(0.736-0.995) Antiviral therapy for HCB or HCV (yes, no) 0.912(0.785-1.059) No. of disease sites at baseline (1, 2, ≥3) 0.878(0.755-1.020) Etiology (HBV, HCV, alcohol) 0.855 (0.721-1.013)Underlying cirrhosis (yes, no) 0.916 (0.789-1.063) BCLC staging (stageB, stage C) 0.918 (0.791-1.067) Prior procedure (yes, no) 0.902(0.777-1.048) AFP, alpha-fetoprotein; BCLC, Barcelona Clinic LiverCancer; ECOG-PS, Eastern Cooperative Oncology Group performance status;HBV, hepatitis B virus; HCV, hepatitis C virus.

Of note, 32.6% patients in the lenvatinib arm and 38.7% in the sorafenibarm received a post-study anticancer medication (includinginvestigational therapy). Of these, 25.3% of patients in the lenvatinibarm and 11.8% in the sorafenib arm, respectively, received sorafenibduring survival follow-up. In the Western region, 26.1% of patients inthe lenvatinib arm received any anticancer medication during survivalfollow-up versus 38.9% in the sorafenib arm (Table 4).

TABLE 8 Table 4. Post-study Anticancer Therapy During SurvivalFollow-up. Lenvatinib Sorafenib Asia- Asia- Pacific Western PacificWestern Subgroup Subgroup Total Subgroup Subgroup Total (N = 321) (N =157) (N = 478) (N = 319) (N = 157) (N = 478) Received any 115 41 156 12361 184 anticancer (35.8) (26.1) (32.6) (38.6) (38.9) (38.7) medication(not given for any procedure) during survival follow-up - no. (%)Underwent any 111 11 122 112 18 130 anticancer procedure (34.6) (7.0)(25.5) (35.1) (11.5) (27.3) during survival follow-up - no. (%)

In the lenvatinib area, 7.0% of patients in the Western region had anyanticancer procedure during follow-up compared with 11.0% of patients inthe sorafenib arm in this region.

Safety and Side-effect Profile

Median duration of study treatment for patients in the lenvatinib groupwas longer than for patients in the sorafenib group (5.7 vs. 3.7months). Treatment-emergent adverse events occurred in 98.7% of patientswho received lenvatinib and 99.4% of patients who received sorafenib.Adjusted by patient-years, the adverse event rate was 18.9 in thelenvatinib group and 19.7 in the sorafenib group. Treatment-emergentadverse events of grade 3 or higher occurred in 75.0% of patients whoreceived lenvatinib and 66.5% of patients who received sorafenib(adverse event rate: 3.2 vs. 3.3). The most common treatment-emergentadverse events among patients who received lenvatinib (at a dosage of 8mg or 12 mg per day) were hypertension (8 mg per day, 43.0%; 12 mg perday, 41.8%), diarrhea (35.1%; 40.3%), decreased appetite (33.1%; 34.5%),and decreased weight (28.5%; 32.0%). In the sorafenib arm, the mostcommon treatment-emergent adverse events were palmar-plantarerythrodysesthesia (52.4%), diarrhea (46.3%), hypertension (30.3%), anddecreased appetite (26.7%) (Table 5).

TABLE 5 Adverse Events. Lenvatinib (N = 476) Sorafenib (N = 475) Totaltreatment- 447 (93.9)  452 (95.42) related treatment- emergent adverseevents- no. (%) Treatment-related 270 (56.7) 231 (48.6)treatment-emergent adverse events of grade ≥3- no. (%) Serioustreatment- 205 (43.1) 144 (30.3) emergent adverse events - no. (%)Treatment emergent adverse events occurring in ≥15% of patients ineither treatment group Any grade Grade ≥ 3 Any grade Grade ≥ 3 Number ofpatients (percent) Palmar-plantar 128 (26.9) 14 (2.9) 249 (52.4)  54(11.4) erythrodysesthesia Diarrhea 184 (38.7) 20 (4.2) 220 (46.3) 20(4.2) Hypertension 201 (42.2) 111 (23.3) 144 (30.3)  68 (14.3) Decreasedappetite 162 (34.0) 22 (4.6) 127 (26.7)  6 (1.3) Decreased weight 147(30.9) 36 (7.6) 106 (22.3) 14 (2.9) Fatigue 141 (29.6) 18 (3.8) 119(25.1) 17 (3.6) Alopecia 14 (2.9) 0 (0)  119 (25.1) 0 (0)  Proteinuria117 (24.6) 27 (5.7)  54 (11.4)  8 (1.7) Dysphonia 113 (23.7)  1 (0.2) 57 (12.0) 0 (0)  Nausea  93 (19.5)  4 (0.8)  68 (14.3)  4 (0.8)Abdominal pain  81 (17.0)  8 (1.7)  87 (18.3) 13 (2.7) Decreasedplatelet  87 (18.3) 26 (5.5)  58 (12.2) 16 (3.4) count Elevatedaspartate  65 (13.7) 24 (5.0)  80 (16.8) 38 (8.0) aminotransferaseHypothyroidism  78 (16.4) 0 (0)   8 (1.7) 0 (0)  Vomiting  77 (16.2)  6(1.3) 36 (7.6)  5 (1.1) Constipation  76 (16.0)  3 (0.6)  52 (10.9) 0(0)  Rash 46 (9.7) 0 (0)   76 (16.0)  2 (0.4)

Fatal adverse events occurred throughout treatment and appeared to occurat similar rates in both arms. Fatal adverse events determined by theinvestigator to be related to lenvatinib treatment occurred in 11patients (2.3%) and included hepatic failure (3 patients), cerebralhemorrhage (3 patients), and respiratory failure (2 patients). In thesorafenib group, treatment-related fatal adverse events occurred in 4patients (0.8%) and included tumor hemorrhage, ischemic stroke,respiratory failure, and sudden death (1 event per patient).

Lenvatinib dose reduction, drug interruption, and discontinuation due toadverse events occurred in 184 (38.7%), 248 (52.1%), and 94 (19.7%)patients, respectively. In the sorafenib arm, dose reduction, druginterruption, and discontinuation due to adverse events occurred in 185(38.9%), 193 (40.6%), and 69 (14.5%) patients, respectively. The meanlenvatinib dose intensity was 7.0 mg (87.7%) in the 8 mg/day group and10.5 mg (87.5%) in the 12 mg/day group. The mean sorafenib doseintensity was 663.8 mg (83.0%).

Quality of Life

Baseline scores on the EORTC QLQ-C30 and EORTC QLQ-HCC18 healthquestionnaires were similar in the lenvatinib and sorafenib treatmentgroups (FIG. 15). Following treatment, scores declined in both groups.The analysis of time to clinically meaningful deterioration showed thatthe role functioning, pain, and diarrhea from QLQ-C30 and nutrition andbody image from QLQ-HCC18 deterioration was observed earlier in patientstreated with sorafenib than with lenvatinib (nominal P<0.05).

Patients who received lenvatinib experienced fewer instances ofpalmar-plantar erythrodysesthesia, diarrhea, and alopecia and moreinstances of hypertension, proteinuria, dysphonia, and hypothyroidismthan did patients who received sorafenib. Although quality of lifescores declined in both groups after treatment, a clinically meaningfuldelay in deterioration for multiple domains was observed with lenvatinibcompared with sorafenib.

The median duration of lenvatinib treatment was 1.5 times longer thanthat of sorafenib, which may have contributed to the higher incidence ofadverse events. When adjusted for treatment duration, almost allepisodes were comparable for the lenvatinib and sorafenib arms. Thedosages of lenvatinib for HCC (8 or 12 mg per day based on body weight)are lower than the lenvatinib dosage for radioiodine-refractorydifferentiated thyroid cancer (24 mg per day). In the phase 1 study oflenvatinib in HCC, patients with HCC who received 12 mg of lenvatinibper day and patients with solid tumors who received 25 mg of lenvatinibper days had similar lenvatinib plasma concentration at 24 hours,possibly because lenvatinib is metabolized in the liver. In the currentphase 3 study, similar clinical activities and safety profiles wereobserved for both the 8 mg and 12 mg per day lenvatinib startingdosages.

In conclusion, the results of this study demonstrated noninferiority oflenvatinib in overall survival to sorafenib and statisticallysignificant and clinically meaningful improvement in progression-freesurvival, time to progression, and objective response rate. The safetyprofiles of lenvatinib and sorafenib in this study appear consistentwith the known safety profiles of these agents in HCC and no new safetysignals were identified. Based on these results, lenvatinib may be apotential treatment option in advanced HCC.

Example 2: Dose Interruption and Dose Reduction for Lenvatinib Toxicity

Lenvatinib capsules were taken orally, once daily (QD) in continuous28-day cycles. The dose of lenvatinib was based on the subject'sbaseline body weight (13W) as shown below.

TABLE 10 Drug Baseline Oral Dose Number Dispensed Name BW Strength Formand Frequency Lenvatinib ≥60 kg 12 mg capsule 3 × 4-mg capsules, oncedaily at the same time each day <60 kg  8 mg capsule 2 × 4-mg capsules,once daily at the same time each day

Lenvatinib toxicity was managed by treatment interruption, dosereduction, and/or treatment discontinuation. Dose adjustment formanagement of lenvatinib toxicity (with the exception of hypertension)was done in accordance with Table 6.

TABLE 6 Lenvatinib Dose Reductions and Interruption Instructions Dosereductions occurred in succession based on the previous dose level (12,8, and 4 mg/day, and 4 mg every other day [QOD]). Any dose reductionbelow 4 mg QOD was discussed with the sponsor. Once the dose wasreduced, it was not increased at a later date. Nonhematologic ToxicitiesTreatment-Related Toxicity^(a,b) Management Dose Adjustment Grade 1 orTolerable Grade 2 Continue treatment^(c) No change Intolerable Grade2^(c) or Grade 3^(d,e) First occurrence Interrupted until resolved toOne-level reduction Grade 0-1 or baseline Second occurrence Interrupteduntil resolved to One-level reduction (same toxicity or new toxicity)Grade 0-1 or baseline Third occurrence^(f) Interrupted until resolved toOne-level reduction (same toxicity or new toxicity) Grade 0-1 orbaseline Fourth occurrence Interrupted until resolved to Discuss withsponsor (same toxicity or new toxicity) Grade 0-1 or baseline Grade4:^(g) Discontinue Lenvatinib Hematologic Toxicities and ProteinuriaTreatment-Related Toxicity^(a) Management Dose Adjustment Grade 1 orGrade 2^(e) Continue treatment^(c) No change Grade 3^(e) Firstoccurrence Interrupted until resolved to No change Grade 0-2 or BaselineSecond occurrence Interrupted until resolved to One-level reduction(same toxicity or new toxicity) Grade 0-2 or Baseline Third occurrenceInterrupted until resolved to One-level reduction (same toxicity or newtoxicity) Grade 0-2 or Baseline Fourth occurrence^(f) Interrupted untilresolved to One-level reduction (same toxicity or new toxicity) Grade0-2 or Baseline Fifth occurrence Interrupted until resolved to Discusswith sponsor (same toxicity or new toxicity) Grade 0-2 or Baseline Grade4 First occurrence Interrupted until resolved to One-level reductionGrade 0-2 or Baseline Second occurrence Interrupted until resolved toOne-level reduction (same toxicity or new toxicity) Grade 0-2 orBaseline Third occurrence^(f) Interrupted until resolved to One-levelreduction (same toxicity or new toxicity) Grade 0-2 or Baseline Fourthoccurrence Interrupted until resolved to Discuss with sponsor (sametoxicity or new toxicity) Grade 0-2 or Baseline Note: Grading accordingto CTCAE v4.0. ALP = alkaline phosphatase; ALT = alanineaminotransferase; AST = aspartate aminotransferase; CTCAE v4.0 = CommonTerminology Criteria for Adverse Events Version 4.0; ULN = upper limitof normal; γ-GTP = international normalized ratio. ^(a)An interruptionof lenvatinib for more than 28 days (due to treatment-relatedtoxicities) required sponsor's approval before treatment was resumed.During treatment interruption, AE assessment was repeated at least every7 days (until administration was restarted). ^(b)Initiated optimalmedical management for nausea, vomiting, diarrhea, and/or hypothyroidismprior to any lenvatinib treatment, interruption, or dose reduction.^(c)Grade 2 toxicities were determined to be tolerable or intolerable byboth the subject and investigator. If the Grade 2 toxicity wasdetermined to be intolerable, the dose of study drug was reduced with orwithout dose interruption. Interruption for Grade 3 toxicity wasmandatory. ^(d)Obese subjects with weight loss did not need to return tobaseline or Grade 1 weight loss to restart lenvatinib. If there was noweight loss for at least 1 week, subjects were restarted at the lowerdose, and normal body mass index was used for further dose reductions.^(e)Not applicable to abnormal clinical laboratory values that were notclinically relevant based on the judgment of the investigator (e.g.,ALT, AST, γ-GTP values <10 × ULN, and sodium). ^(f)Not applicable forsubjects who started at 8 mg QD. ^(g)Excluding laboratory abnormalitiesjudged to be non-life-threatening, which were managed as Grade 3.

Management of Hypertension

Hypertension is a recognized side effect of treatment with drugsinhibiting vascular endothelial growth factor (VEGF) signaling. Subjectsenrolled in the trial had BP <=150/90 mm Hg at the time of study entryand, if they were known to be hypertensive, had been on a stable dose ofantihypertensive therapy for at least 1 week before Cycle 1/Day 1. Earlydetection and effective management of hypertension were important tominimize the need for lenvatinib dose interruptions and reductions.

Antihypertensive agents were started as soon as elevated BP (systolicBP >=140 mm Hg or diastolic BP >=90 mm Hg) was confirmed on 2assessments a minimum of 1-hour apart. One BP assessment was defined asthe mean value of 3 measurements at least 5 minutes apart. The choice ofantihypertensive treatment was individualized to the subject's clinicalcircumstances and followed standard medical practice. For previouslynormotensive subjects, appropriate antihypertensive therapy was startedwhen systolic BP >=140 mm Hg or diastolic BP >=90 mm Hg was firstobserved on 2 assessments a minimum of 1-hour apart. For those subjectswho were already on antihypertensive medication, treatment modificationmay have been necessary if hypertension persisted. For subjects withhypertension and proteinuria, appropriate therapy, e.g.,angiotensin-converting enzyme inhibitor or angiotensin-II receptorantagonist was preferred.

Lenvatinib was withheld in any instance where a subject was at imminentrisk to develop a hypertensive crisis or had significant risk factorsfor severe complications of uncontrolled hypertension (e.g.,BP >=160/100 mm Hg, significant risk factors for cardiac disease,intracerebral hemorrhage, or other significant co-morbidities). Once thesubject was on the same antihypertensive medications for at least 48hours and the BP was controlled, lenvatinib was resumed as describedbelow.

During the Treatment Period, both in the Randomization Phase and in theExtension

Phase, subjects with systolic BP >=160 mm Hg or diastolic BP >=100 mm Hghad their BP monitored every 2 weeks (on Day 15 or more frequently asclinical indicated) until systolic BP was <=150 mm Hg and diastolic BPwas <=95 mm Hg for 3 consecutive months. If a repeat event of systolicBP >=160 mm Hg or diastolic BP >=100 mm Hg occurred, the subject resumedthe Day 15 evaluation until systolic BP was <=150 mm Hg and diastolic BPwas <=95 mm Hg for 3 consecutive months.

The following guidelines were followed for the management of systolicBP >=160 mm Hg or diastolic BP >=100 mm Hg confirmed on repeatmeasurements after 1 hour:

Lenvatinib was continued and antihypertensive therapy was instituted forsubjects not already receiving antihypertensive medication

For those subjects already on antihypertensive medication, dose ormedication choice was modified as per the investigator.

If systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg persisted despitemaximal antihypertensive therapy, then lenvatinib administration wasinterrupted and restarted at a dose of 8 mg QD (one dose level reductionas specified in Table 6) only when systolic BP <=150 mm Hg and diastolicBP <=95 mm Hg and the subject was on a stable dose of antihypertensivemedication for at least 48 hours.

If systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg recurred on the8-mg QD dose despite optimal management of hypertension withantihypertensive medications (either by dose increase or the addition ofa different class of antihypertensive), then lenvatinib administrationwas interrupted and restarted at a dose of 4-mg QD (1 more dose levelreduction as specified in Table 6) only when systolic BP <=150 mm Hg anddiastolic BP <=95 mm Hg and the subject was on a stable dose ofantihypertensive medication for at least 48 hours.

If systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg recurred on the4-mg QD dose despite optimal management of hypertension withantihypertensive medications (either by dose increase or the addition ofa different class of antihypertensive), then lenvatinib administrationwas interrupted and restarted at a dose of 4-mg QOD (1 more dose levelreduction as specified in Table 6) only when systolic BP <=150 mm Hg anddiastolic BP <=95 mm Hg and the subject was on a stable dose ofantihypertensive medication for at least 48 hours.

If systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg recurred on the4-mg QOD dose despite optimal management of hypertension withantihypertensive medications (either by dose increase or the addition ofa different class of antihypertensive), then lenvatinib administrationwas interrupted and restart of study medication was discussed with thesponsor.

The following guidelines were followed for the management of Grade 4hypertension (life-threatening consequences):

Appropriate medical management was instituted.

Study drug was discontinued.

Management of Proteinuria

Regular assessment for proteinuria was conducted. Guidelines forassessment and management of proteinuria were as follows:

Initial episode of proteinuria: If proteinuria >=2+ was detected onurine dipstick testing, study drug was continued and a 24-hour urinecollection for total protein was obtained as soon as possible within 72hours to verify the grade of proteinuria. Grading according to CTCAEv4.0 was based on the 24-hour urine collection for total protein result.Additionally, a spot protein-creatinine ratio test was performed on the24-hour urine sample as soon as possible within 72 hours. Management oflenvatinib administration was based on the grade of proteinuriaaccording to 7.

During the Treatment Period, both in the Randomization Phase and theExtension Phase, urine dipstick testing for subjects withproteinuria >=2+ was performed every 2 weeks (on Day 15 or morefrequently as clinically indicated) until the results were 1+ ornegative for 3 consecutive months. Any subsequent increases in the levelof proteinuria >=2+ on urine dipstick testing were confirmed with a24-hour urine collection and graded according to the dose reduction andinterruption instructions provided in 7. A spot protein-creatinine ratiotest was performed on the 24 hour urine sample as soon as possible. If anew event of proteinuria >=2+ occurred, the subject resumed the Day 15urine dipstick testing for evaluation of proteinuria until results were1+ or negative for 3 consecutive months.

A 24-hour urine collection for protein quantitation was required in thefollowing situations:

The first (initial) occurrence of 2+, 3+, or 4+ proteinuria on urinedipstick while on study drug

A subsequent apparent increase in severity of urine dipstick proteinuria(from the prior measurement which was >=2+) occurring on the samelenvatinib dose level

When there was a lenvatinib dose reduction and on follow-up, the urineprotein dipstick result is 2+, 3+, or 4+ (at the new dose level)

The 24-hour urine collection was not required in the followingsituations:

Persistence of the same severity of proteinuria by urine dipstick at thesame study dose level when a 24-hour urine collection has already beencollected at that dose level)

Subsequent occurrences of 2+, 3+, or 4+ proteinuria by urine dipstickwhen the subject was off study drug

Management of Hepatotoxicity

Regular monitoring of liver function tests (e.g., alanine transaminase[ALT], aspartate transaminase [AST], bilirubin levels) was conducted asclinically indicated. If signs occurred indicating a decrease in liverfunction by 1 grade or more from Baseline, the instructions in Table 6were followed. Appropriate supportive care was provided together withclose monitoring. If hepatic failure occurred the study drug wasdiscontinued.

Management of Thromboembolic Events

Subjects were advised to pay attention to the symptoms suggestive ofvenous thromboembolic events, which included acute onset of dyspnea,chest pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, anddeep vein thrombosis signs including lower extremity swelling, redness,and warmth to touch or tenderness. If any of these signs or symptomsappeared, subjects were instructed to report such signs and symptomspromptly to the treating physician. If a thromboembolic event wasconfirmed, instructions contained in Table 6 were followed. If a subjectexperienced life-threatening (Grade 4) thromboembolic reactions,including pulmonary embolism, the study drug was discontinued.

Management of Posterior Reversible Encephalopathy Syndrome

In clinical studies with lenvatinib, events of posterior reversibleencephalopathy syndrome (PRES), a neurological disorder that can presentwith headache, seizure, lethargy, confusion, altered mental function,blindness, and other visual or neurological disturbances, were reportedin less than 1% of lenvatinib-treated subjects. Mild to severehypertension also could be present. A magnetic resonance imaging (MRI)was necessary to confirm the diagnosis of PRES. In subjects with signsor symptoms of PRES, appropriate measures were to be taken to controlblood pressure, and instructions in Table 6 were followed.

Example 3: Adverse Events that Required Dose Reduction or Interruptionof Study Drug

A summary of TEAEs occurring in >=10% of subjects in the lenvatinib orsorafenib treatment arm, in decreasing order of frequency in the totallenvatinib arm, is presented in Table 7.

TABLE 7 Treatment-emergent Adverse Events Occurring in at Least 10% ofSubjects in Either Treatment Arm, by Preferred Term Lenvatinib 8 mg ^(a)12 mg ^(a) Total Sorafenib (N = 151) (N = 325) (N = 476) (N = 475)Preferred Term n (%) n (%) n (%) n (%) Subjects with Any TEAEs 151(100.0) 319 (98.2)  470 (98.7)  472 (99.4)  Hypertension 65 (43.0) 136(41.8)  201 (42.2)  144 (30.3)  Diarrhea 53 (35.1) 131 (40.3)  184(38.7)  220 (46.3)  Decreased appetite 50 (33.1) 112 (34.5)  162 (34.0) 127 (26.7)  Weight decreased 43 (28.5) 104 (32.0)  147 (30.9)  106(22.3)  Fatigue 42 (27.8) 99 (30.5) 141 (29.6)  119 (25.1) Palmar-plantar erythrodysesthesia 35 (23.2) 93 (28.6) 128 (26.9)  249(52.4)  syndrome Proteinuria 37 (24.5) 80 (24.6) 117 (24.6)  54 (11.4)Dysphonia 28 (18.5) 85 (26.2) 113 (23.7)  57 (12.0) Nausea 24 (15.9) 69(21.2) 93 (19.5) 68 (14.3) Platelet count decreased 26 (17.2) 61 (18.8)87 (18.3) 58 (12.2) Abdominal pain 19 (12.6) 62 (19.1) 81 (17.0) 87(18.3) Hypothyroidism 25 (16.6) 53 (16.3) 78 (16.4) 8 (1.7) Vomiting 22(14.6) 55 (16.9) 77 (16.2) 36 (7.6)  Constipation 19 (12.6) 57 (17.5) 76(16.0) 52 (10.9) Blood bilirubin increased 23 (15.2) 48 (14.8) 71 (14.9)63 (13.3) Pyrexia 24 (15.9) 45 (13.8) 69 (14.5) 63 (13.3) Ascites 21(13.9) 47 (14.5) 68 (14.3) 44 (9.3)  Edema peripheral 23 (15.2) 43(13.2) 66 (13.9) 33 (6.9)  Aspartate aminotransferase increased 21(13.9) 44 (13.5) 65 (13.7) 80 (16.8) Abdominal pain upper 21 (13.9) 37(11.4) 58 (12.2) 40 (8.4)  Asthenia 14 (9.3)  40 (12.3) 54 (11.3) 48(10.1) Alanine aminotransferase increased 17 (11.3) 36 (11.1) 53 (11.1)52 (10.9) Back pain 11 (7.3)  39 (12.0) 50 (10.5) 31 (6.5)  Rash 18(11.9) 28 (8.6)  46 (9.7)  76 (16.0) Stomatitis 11 (7.3)  34 (10.5) 45(9.5)  56 (11.8) Alopecia 5 (3.3) 9 (2.8) 14 (2.9)  119 (25.1)  [Datacutoff date: Nov. 13, 2016; Percentages are based on the total number ofsubjects within the relevant treatment group in the Safety Analysis Set.Display is in decreasing order of frequency of TEAEs in the lenvatinibtotal group. Subjects with 2 or more TEAEs in the same preferred termwere counted only once. Adverse Event terms were coded using MedDRAversion 19.1. MedDRA = Medical Dictionary for Regulatory Activities;TEAE = treatment-emergent adverse event. ^(a) 8 mg and 12 mg were thelenvatinib starting doses based on the subjects' body weight (<60 kg,≥60 kg) at Baseline.]

A TEAE occurred in all but 6 and 3 subjects in the lenvatinib andsorafenib arms, respectively. The most frequently reported IEAEs (>30%of subjects) were hypertension, diarrhea, decreased appetite, and weightdecreased for lenvatinib and palmar-plantar erythrodysaesthesia (PPE)syndrome, diarrhea, and hypertension for sorafenib. Adverse events thatoccurred in >=10% more subjects in the lenvatinib arm than in thesorafenib arm were: hypertension (42.2% vs 30.3%), proteinuria (24.6% vs11.4%), dysphonia (23.7% vs 12.0%), and hypothyroidism (16.4% vs 1.7%).These AEs are consistent with the known safety profile of lenvatinib inother cancer indications. Other AEs with a subject incidence of <10% butthat were reported in a higher proportion of lenvatinib-treated subjectscompared with sorafenib (>=10 episodes in 1 treatment arm and adifference between treatments of >=0.1 episodes per SY) when adjusted bytreatment duration included: proteinuria (0.5 vs 0.31 episodes per SY),dysphonia (0.4 vs 0.28), hypothyroidism (0.24 vs 0.03), WBC countdeceased (0.25 vs 0.15), neutrophil count decreased (0.21 vs 0.06), andhepatic encephalopathy (0.17 vs 0.04).

An algorithm of dose interruption followed by dose reduction was usedfor the management of lenvatinib toxicity (see, Table 6). Unadjusted fortreatment duration, adverse events (AEs) leading to dose reduction orinterruption were reported in 61.8% of subjects in the lenvatinib armand 55.6% of subjects in the sorafenib arm (Table 8).

TABLE 8 Treatment-emergent Adverse Events Leading to DoseReduction/Interruption of Study Drug in at Least 1% of Subjects inEither Treatment Arm, by System Organ Class and Preferred Term - SafetyAnalysis Set Lenvatinib 8 mg ^(a) 12 mg ^(a) Total Sorafenib SystemOrgan Class (N = 151) (N = 325) (N = 476) (N = 475) Preferred Term n (%)n (%) n (%) n (%) Subjects with any TEAEs leading to 81 (53.6) 213(65.5)  294 (61.8) 264 (55.6)  Dose Reduction or Interruption Blood andlymphatic system disorders 5 (3.3) 11 (3.4)  16 (3.4) 13 (2.7) Neutropenia 0 (0.0) 6 (1.8)  6 (1.3) 0 (0.0) Thrombocytopenia 2 (1.3) 4(1.2)  6 (1.3) 4 (0.8) Anemia 2 (1.3) 1 (0.3)  3 (0.6) 8 (1.7)Gastrointestinal disorders 22 (14.6) 65 (20.0)  87 (18.3) 72 (15.2)Diarrhea 8 (5.3) 28 (8.6)  36 (7.6) 35 (7.4)  Nausea 2 (1.3) 14 (4.3) 16 (3.4) 9 (1.9) Vomiting 1 (0.7) 11 (3.4)  12 (2.5) 6 (1.3) Ascites 3(2.0) 7 (2.2) 10 (2.1) 5 (1.1) Abdominal pain 2 (1.3) 4 (1.2)  6 (1.3) 8(1.7) Stomatitis 2 (1.3) 4 (1.2)  6 (1.3) 2 (0.4) Abdominal pain upper 2(1.3) 3 (0.9)  5 (1.1) 2 (0.4) Esophageal varices hemorrhage 0 (0.0) 5(1.5)  5 (1.1) 1 (0.2) General disorders and administration 17 (11.3) 50(15.4)  67 (14.1) 35 (7.4)  site conditions Fatigue 5 (3.3) 22 (6.8)  27(5.7) 17 (3.6)  Asthenia 3 (2.0) 13 (4.0)  16 (3.4) 9 (1.9) Pyrexia 4(2.6) 8 (2.5) 12 (2.5) 5 (1.1) Edema peripheral 2 (1.3) 4 (1.2)  6 (1.3)3 (0.6) Malaise 2 (1.3) 3 (0.9)  5 (1.1) 0 (0.0) Hepatobiliary disorders2 (1.3) 25 (7.7)  27 (5.7) 19 (4.0)  Hepatic function abnormal 0 (0.0) 2(0.6)  2 (0.4) 9 (1.9) Investigations 24 (15.9) 57 (17.5)  81 (17.0) 52(10.9) Platelet count decreased 9 (6.0) 13 (4.0)  22 (4.6) 12 (2.5) Blood bilirubin increased 8 (5.3) 12 (3.7)  20 (4.2) 14 (2.9)  Weightdecreased 3 (2.0) 17 (5.2)  20 (4.2) 4 (0.8) Neutrophil count decreased4 (2.6) 7 (2.2) 11 (2.3) 5 (1.1) Aspartate aminotransferase increased 4(2.6) 5 (1.5)  9 (1.9) 18 (3.8)  Gamma-glutamyltransferase increased 1(0.7) 6 (1.8)  7 (1.5) 4 (0.8) Alanine aminotransferase increased 2(1.3) 4 (1.2)  6 (1.3) 9 (1.9) White blood cell count decreased 3 (2.0)3 (0.9)  6 (1.3) 4 (0.8) Metabolism and nutrition disorders 21 (13.9) 31(9.5)   52 (10.9) 19 (4.0)  Decreased appetite 15 (9.9)  21 (6.5)  36(7.6) 15 (3.2)  Dehydration 3 (2.0) 3 (0.9)  6 (1.3) 0 (0.0)Hyponatremia 2 (1.3) 3 (0.9)  5 (1.1) 0 (0.0) Musculoskeletal andconnective 4 (2.6) 14 (4.3)  18 (3.8) 9 (1.9) tissue disorders Myalgia 1(0.7) 4 (1.2)  5 (1.1) 0 (0.0) Nervous system disorders 7 (4.6) 28(8.6)  35 (7.4) 14 (2.9)  Hepatic encephalopathy 4 (2.6) 16 (4.9)  20(4.2) 3 (0.6) Renal and urinary disorders 5 (3.3) 35 (10.8) 40 (8.4) 9(1.9) Proteinuria 4 (2.6) 29 (8.9)  33 (6.9) 7 (1.5) Respiratory,thoracic and 4 (2.6) 12 (3.7)  16 (3.4) 12 (2.5)  mediastinal disordersDyspnea 2 (1.3) 6 (1.8)  8 (1.7) 4 (0.8) Skin and subcutaneous tissue 5(3.3) 23 (7.1)  28 (5.9) 111 (23.4)  disorders Palmar-plantarerythrodysesthesia 4 (2.6) 21 (6.5)  25 (5.3) 88 (18.5) syndrome Rash 0(0.0) 2 (0.6)  2 (0.4) 10 (2.1)  Rash maculo-papular 0 (0.0) 0 (0.0)  0(0.0) 5 (1.1) Vascular disorders 3 (2.0) 30 (9.2)  33 (6.9) 19 (4.0) Hypertension 3 (2.0) 26 (8.0)  29 (6.1) 18 (3.8)  [The data cutoff datefor this table was Nov. 13, 2016. Percentages are based on the totalnumber of subjects within the relevant treatment group in the SafetyAnalysis Set. Subjects with 2 or more TEAEs reported in the same systemorgan class or preferred term were only counted once. Adverse Eventsterms were coded using MedDRA version 19.1. MedDRA = Medical Dictionaryfor Regulatory Activities; TEAE = treatment-emergent adverse event. ^(a)8 mg and 12 mg were the lenvatinib starting doses based on the subjects'body weight (<60 kg, ≥60 kg) at baseline.]

Adverse events leading to dose reduction or interruption of lenvatinibwere most frequently (>=10% of subjects) coded to the SOCs ofGastrointestinal disorders (18.3%), Investigations (17.0%), Generaldisorders and Administration Site Conditions (14.1%), and Metabolism andNutrition disorders (10.9%).

Adverse events that led to dose reduction or interruption in 5% or moreof subjects in the lenvatinib or sorafenib arm, respectively, weredecreased appetite (7.6% vs 3.2%), diarrhea (7.6% vs 7.4%), proteinuria(6.9% vs 1.5%), hypertension (6.1% vs 3.8%), fatigue (5.7% vs 3.6%), andPPE syndrome (5.3% vs 18.5%). Except for PPE syndrome, which occurredmore frequently with sorafenib, these treatment-emergent adverse events(TEAEs) led to dose modification either at similar rates in the 2treatment arms, or at a higher frequency in the lenvatinib arm.

Other TEAEs that led to dose modification in a higher percentage ofsubjects in the lenvatinib arm (total incidence >2% to <5% but[approximately] >2 times the rate) than in the sorafenib arm werehepatic encephalopathy (4.2% vs 0.6%), weight decreased (4.2% vs 0.8%),pyrexia (2.5% vs 1. 1 %), vomiting (2.5% vs 1.3%), neutrophil countdecreased (2.3% vs 1.1%), and ascites (2.1% vs 1.1%). The only TEAE thatled to dose modification in a higher percentage of subjects in thesorafenib arm (total incidence >2% to <5% but at least double the rate)than in the lenvatinib arm was AST increased (3.8% vs 1.9%).

As of the data cutoff date for the primary analysis, the majority ofsubjects had ended treatment; treatment was ongoing for 27 (5.6%)lenvatinib and 25 (5.3%) sorafenib subjects. The most frequent reasonfor discontinuation of treatment was disease progression. Fewer subjectsended treatment due to disease progression in the lenvatinib arm (311;65.1%) than in the sorafenib arm (347; 72.9%). Adverse events were citedby the investigators as the reason for ending treatment in 13.2% (n=63)of lenvatinib and 9.0% (n=43) of sorafenib subjects (see, Table 9).

TABLE 9 Subject Disposition and Reasons for Discontinuation of Treatmentduring Randomization Phase Lenvatinib Sorafenib Total (N = 478) (N =476) (N = 954) n (%) n (%) n (%) Randomized 478 (100.0)  476 (100.0) 954 (100.0) Not treated 2 (0.4)  1 (0.2)  3 (0.3) Treated 476 (99.6) 475 (99.8) 951 (99.7) Treatment ongoing at 27 (5.6)  25 (5.3) 52 (5.5)data cutoff date Discontinued Treatment ^(b) 451 (94.4)  451 (94.7) 902(94.5) Primary Reason for Discontinuation of Treatment DiseaseProgression 311 (65.1)  347 (72.9) 658 (69.0) Adverse event 63 (13.2) 43(9.0) 106 (11.1) Subject choice 28 (5.9)  15 (3.2) 43 (4.5) Lost tofollow-up 3 (0.6)  1 (0.2)  4 (0.4) Withdrawal of consent 9 (1.9)  5(1.1) 14 (1.5) Other ^(a) 37 (7.7)  40 (8.4) 77 (8.1) DiscontinuedTreatment but 82 (17.2)  82 (17.2) 164 (17.2) in Survival Follow-up Datacutoff date: Nov. 13, 2016. Percentages are based on the total number ofsubjects within the relevant treatment group in the Full Analysis Set.^(a) These reasons were collected as investigator comments under the“Other” category in the case report form. ^(b) Includes the 3 subjectswho were not treated after randomization.

The percentage of the subjects who discontinued lenvatinib treatment dueto adverse events was 13.2% (n=62). This low percentage ofdiscontinuation could not have been achieved without the use of dosemodifications (see Table 6).

Example 4: Efficacy Results in Hepatocellular Carcinoma Clinical Study

The efficacy of LENVIMA was evaluated in a randomized, open-label,multicenter, international study (REFLECT; NCT0761266) conducted inpatients with previously untreated unresectable hepatocellular carcinoma(HCC). The study enrolled adults with Child-Pugh A and Barcelona ClinicLiver Cancer (BCLC) Stage C or B HCC who were ineligible for localliver-directed therapy; had an ECOG PS of 0 or 1; had received no priorsystemic therapy for HCC; and had at least one measurable target lesionaccording to modified RECIST for HCC. Efficacy results are summarized inTable 10.

TABLE 10 Efficacy Results in Hepatocellular Carcinoma in REFLECT LENVIMASorafenib N = 478 N = 476 Overall Survival Number of deaths (%) 351 (73)350 (74) Median OS in months 13.6 (12.1, 14.9) 12.3 (10.4, 13.9) (95%CI) Hazard Ratio (95% CI)^(a) 0.92 (0.79, 1.06) Progression-FreeSurvival^(b) (mRECIST) Number of Events (%) 311 (65) 323 (68) Median PFSin months 7.3 (5.6, 7.5) 3.6 (3.6, 3.7) (95% CI) Hazard Ratio (95%CI)^(a) 0.64 (0.55, 0.75) P-value <0.001 Objective Response Rate^(b)(mRECIST) Objective response rate 41% 12% Complete responses, n (%) 10(2.1) 4 (0.8) Partial responses, n (%) 184 (38.5) 55 (11.6) 95% CI (36%,45%) (9%, 15%) Odds Ratio (95% CI) 5.01 (3.59, 7.01) P-value <0.001Progression-Free Survival^(b) (RECIST 1.1) Number of Events (%) 307 (64)320 (67) Median PFS in months 7.3 (5.6, 7.5) 3.6 (3.6, 3.9) (95% CI)Hazard Ratio (95% CI)^(a) 0.65 (0.56, 0.77) Objective Response Rate^(b)(RECIST 1.1) Objective response rate 19%  7% Complete responses, n (%) 2(0.4) 1 (0.2) Partial responses, n (%) 88 (18.4) 30 (6.3) 95% CI (15%,22%) (4%, 9%) Odds Ratio (95% CI) 3.3 (2.2, 5.1)  CI = confidenceinterval; ECOG PS = Eastern Cooperative Oncology Group PerformanceStatus; HR = hazard ratio; OS = overall survival. Non-inferiority marginfor hazard ratio (lenvatinib vs sorafenib) is 1.08. Per independentreview.

Example 5: Drug Interaction Studies: Effect of Lenvatinib on Other Drugs

Clinical Studies with Substrates of CYP3A4 or CYP2C8: There is noprojected significant drug-drug interaction risk between lenvatinib andmidazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate).

In Vitro Studies with Substrates of CYP or UDP-glucuronosyltransferase(UGT): Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19,CYP2D6, and CYP3A. Lenvatinib does not inhibit CYP2A6 and CYP2E1.Lenvatinib induces CYP3A, but it does not induce CYP1A1, CYP1A2, CYP2B6,and CYP2C9.

Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely onlyinhibits UGT1A1 in vivo in the gastrointestinal tract based on theexpression of the enzyme in tissues. Lenvatinib does not inhibit UGT1A6,UGT2B7 or aldehyde oxidase. Lenvatinib does not induce UGTIAI, UGTIA4,UGT1A6, UGT1A9, or UGT2B7.

In Vitro Studies with Substrates of Transporters: Lenvatinib does nothave the potential to inhibit MATE1, MATE2-K, OCTI, OCT2, OAT!, OATS,BSEP, OATP1B1, or OATP1B3 in vivo.

Cross-Reference to Related Applications

This application claims the benefit of priority of U.S. ProvisionalAppl. No. 62/506,900, filed May 16, 2017, the contents of which areincorporated by reference herein in their entirety.

Other Embodiments

While the invention has been described in conjunction with the detaileddescription thereof, the foregoing description is intended to illustrateand not limit the scope of the invention, which is defined by the scopeof the appended claims. Other aspects, advantages, and modifications arewithin the scope of the following claims.

1. A method of treating unresectable hepatocellular carcinoma, themethod comprising administering to a human subject that has anunresectable hepatocellular carcinoma a dosage regimen of lenvatinib ora pharmaceutically acceptable salt thereof that is: (i) 12 mg/day if thebody weight of the human subject is equal to or more than 60 kg or (ii)8 mg/day if the body weight of the human subject is less than 60 kg. 2.(canceled)
 3. The method of claim 1, which is a method of treatingunresectable hepatocellular carcinoma, the method comprisingadministering to a human subject that has an unresectable hepatocellularcarcinoma a first dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject develops an occurrence of a first Grade 3nonhematologic toxicity during treatment with the first dosage regimen,and the method further comprises: (a) terminating administration of thefirst dosage regimen after the occurrence of the first Grade 3nonhematologic toxicity until the first Grade 3 nonhematologic toxicityis resolved to Grade 0-1 or baseline, and administering to the humansubject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject develops an occurrence of a second Grade 3nonhematologic toxicity during treatment with the second dosage regimen;(b) terminating administration of the second dosage regimen after theoccurrence of the second Grade 3 nonhematologic toxicity until thesecond Grade 3 nonhematologic toxicity is resolved to Grade 0-1 orbaseline, and administering to the human subject a third dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 4 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg every other day if the body weight ofthe human subject is less than 60 kg, wherein the human subject developsan occurrence of a third Grade 3 nonhematologic toxicity duringtreatment with the third dosage regimen; and (c) terminatingadministration of the third dosage regimen after the occurrence of thethird Grade 3 nonhematologic toxicity until the third Grade 3nonhematologic toxicity is resolved to Grade 0-1 or baseline, and, ifthe body weight of the human subject is equal to or more than 60 kg,administering to the human subject a fourth dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day.
 4. (canceled)
 5. The method of claim 1, which is amethod of treating unresectable hepatocellular carcinoma, the methodcomprising administering to a human subject that has an unresectablehepatocellular carcinoma a first dosage regimen comprising lenvatinib ora pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject develops an occurrence of a firstpersistent and intolerable Grade 2 or Grade 3 nonhematologic toxicityduring treatment with the first dosage regimen, and the method furthercomprises: (a) terminating administration of the first dosage regimenafter the occurrence of the first persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity until the first persistent andintolerable Grade 2 or Grade 3 nonhematologic toxicity is resolved toGrade 0-1 or baseline, and administering to the human subject a seconddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg, wherein the humansubject develops an occurrence of a second persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity during treatment with thesecond dosage regimen; (b) terminating administration of the seconddosage regimen after the occurrence of the second persistent andintolerable Grade 2 or Grade 3 nonhematologic toxicity until the secondpersistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity isresolved to Grade 0-1 or baseline, and administering to the humansubject a third dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg every other day if the body weight of the human subject isless than 60 kg, wherein the human subject develops an occurrence of athird persistent and intolerable Grade 2 or Grade 3 nonhematologictoxicity during treatment with the third dosage regimen; and (c)terminating administration of the third dosage regimen after theoccurrence of the third persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity until the third persistent and intolerable Grade2 or Grade 3 nonhematologic toxicity is resolved to Grade 0-1 orbaseline, and, if the body weight of the human subject is equal to ormore than 60 kg, administering to the human subject a fourth dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 4 mg every other day.
 6. (canceled)
 7. The methodof claim 1, which is a method of treating unresectable hepatocellularcarcinoma, the method comprising administering to a human subject thathas an unresectable hepatocellular carcinoma a first dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 12 mg/day if the body weight of the human subject is equalto or more than 60 kg or (ii) 8 mg/day if the body weight of the humansubject is less than 60 kg, wherein the human subject develops anoccurrence of a first persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality during treatment with the first dosage regimen, and themethod further comprises: (a) terminating administration of the firstdosage regimen after the occurrence of the first persistent andintolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality until the firstpersistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality is resolved to Grade0-1 or baseline, and administering to the human subject a second dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg, wherein the humansubject develops an occurrence of a second persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade4 laboratory abnormality during treatment with the second dosageregimen; (b) terminating administration of the second dosage regimenafter the occurrence of the second persistent and intolerable Grade 2 orGrade 3 nonhematologic toxicity or non-life-threatening Grade 4laboratory abnormality until the second persistent and intolerable Grade2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4laboratory abnormality is resolved to Grade 0-1 or baseline, andadministering to the human subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 4 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg every other day if the body weight of the humansubject is less than 60 kg, wherein the human subject develops anoccurrence of a third persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality during treatment with the third dosage regimen; and (c)terminating administration of the third dosage regimen after theoccurrence of the third persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality until the third persistent and intolerable Grade 2 or Grade3 nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality is resolved to Grade 0-1 or baseline, and, if the bodyweight of the human subject is equal to or more than 60 kg,administering to the human subject a fourth dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day.
 8. (canceled)
 9. The method of claim 3, wherein thehuman subject develops an occurrence of a Grade 4 nonhematologictoxicity excluding non-life-threatening Grade 4 laboratory abnormalityduring treatment with the first, second, third or fourth dosage regimen,and the method further comprises terminating administration of thedosage regimen after the occurrence of the Grade 4 nonhematologictoxicity excluding the non-life-threatening Grade 4 laboratoryabnormality. 10.-20. (canceled)
 21. The method of claim 3, whereinmedical management of each of the first, second, and third persistentand intolerable Grade 2 or Grade 3 nonhematologic toxicities ornon-life-threatening Grade 4 laboratory abnormality is initiated priorto terminating administration of the dosage regimen administered at thetime of onset of the Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality. 22.-23. (canceled)24. The method of claim 3, wherein the first persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade4 laboratory abnormality is the same as the second and/or thirdpersistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality. 25.-26. (canceled)27. The method of claim 3, wherein the Grade 3 nonhematologic toxicityis selected from the group consisting of Grade 3 hypertension, Grade 3diarrhea, Grade 3 arthralgia, Grade 3 myalgia, Grade 3 decreasedappetite, Grade 3 fatigue, Grade 3 decreased weight, Grade 3 dysphonia,Grade 3 nausea, Grade 3 abdominal pain, Grade 3 QT/QTc intervalprolongation, Grade 3 hypothyroidism, Grade 3 vomiting, Grade 3constipation, Grade 3 rash, and Grade 3 palmar-plantarerythrodysesthesia.
 28. The method of claim 5, wherein the Grade 2 orGrade 3 nonhematologic toxicity is selected from the group consisting ofGrade 3 hypertension, Grade 2 hypertension, Grade 3 diarrhea, Grade 2diarrhea, Grade 3 decreased appetite, Grade 2 decreased appetite, Grade3 arthralgia, Grade 2 arthralgia, Grade 3 myalgia, Grade 2 myalgia,Grade 3 fatigue, Grade 2 fatigue, Grade 3 decreased weight, Grade 2decreased weight, Grade 2 alopecia, Grade 3 dysphonia, Grade 2dysphonia, Grade 3 nausea, Grade 2 nausea, Grade 3 abdominal pain, Grade2 abdominal pain, Grade 3 QT/QTc interval prolongation, Grade 2 QT/QTcinterval prolongation, Grade 3 hypothyroidism, Grade 2 hypothyroidism,Grade 3 vomiting, Grade 2 vomiting, Grade 3 constipation, Grade 2constipation, Grade 3 rash, Grade 2 rash, Grade 3 palmar-plantarerythrodysesthesia, and Grade 2 palmar-plantar erythrodysesthesia. 29.The method of claim 7, wherein the Grade 4 laboratory abnormality isselected from the group consisting of Grade 4 increase in aspartateaminotransferase, Grade 4 increase in alanine aminotransferase, Grade 4increase in alkaline phosphatase, Grade 4 hypokalemia, Grade 4hyponatremia, Grade 4 hypoglycemia, Grade 4 increase in blood bilirubin,and Grade 4 increase in gamma glutamyl transferase. 30.-31. (canceled)32. A method of treating unresectable hepatocellular carcinoma, themethod comprising administering to a human subject that has anunresectable hepatocellular carcinoma: a dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 8 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg/day if the body weight of the human subject isless than 60 kg, wherein the human subject was previously treated with aprior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of (i) 12 mg/day if the body weight ofthe human subject is equal to or more than 60 kg or (ii) 8 mg/day if thebody weight of the human subject is less than 60 kg, and wherein thehuman subject developed an occurrence of a Grade 3 nonhematologictoxicity during treatment with the prior dosage regimen; a dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 4 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg every other day ifthe body weight of the human subject is less than 60 kg, wherein thehuman subject was previously treated with a prior dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 8 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg/day if the body weight of the humansubject is less than 60 kg, and wherein the human subject developed anoccurrence of a Grade 3 nonhematologic toxicity during treatment withthe prior dosage regimen; or a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg every otherday, wherein the body weight of the human subject is equal to or morethan 60 kg, wherein the human subject was previously treated with aprior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 4 mg/day, and wherein the humansubject developed an occurrence of a Grade 3 nonhematologic toxicityduring treatment with the prior dosage regimen.
 33. (canceled)
 34. Amethod of treating unresectable hepatocellular carcinoma, the methodcomprising administering to a human subject that has an unresectablehepatocellular carcinoma: a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a prior dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, and wherein the humansubject developed an occurrence of a persistent and intolerable Grade 2or Grade 3 nonhematologic toxicity during treatment with the priordosage regimen; a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg every other day if the body weight of the human subject isless than 60 kg, wherein the human subject was previously treated with aprior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of (i) 8 mg/day if the body weight ofthe human subject is equal to or more than 60 kg or (ii) 4 mg/day if thebody weight of the human subject is less than 60 kg, and wherein thehuman subject developed an occurrence of a persistent and intolerableGrade 2 or Grade 3 nonhematologic toxicity during treatment with theprior dosage regimen; or a dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of 4 mg every otherday, wherein the body weight of the human subject is equal to or morethan 60 kg, wherein the human subject was previously treated with aprior dosage regimen comprising lenvatinib or a pharmaceuticallyacceptable salt thereof at a dose of 4 mg/day, and wherein the humansubject developed an occurrence of a persistent and intolerable Grade 2or Grade 3 nonhematologic toxicity during treatment with the priordosage regimen.
 35. (canceled)
 36. A method of treating unresectablehepatocellular carcinoma, the method comprising administering to a humansubject that has an unresectable hepatocellular carcinoma: a dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg, wherein the humansubject was previously treated with a prior dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 12 mg/day if the body weight of the human subject is equal to ormore than 60 kg or (ii) 8 mg/day if the body weight of the human subjectis less than 60 kg, and wherein the human subject developed anoccurrence of a persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality during treatment with the prior dosage regimen; a dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 4 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg every other day ifthe body weight of the human subject is less than 60 kg, wherein thehuman subject was previously treated with a prior dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 8 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg/day if the body weight of the humansubject is less than 60 kg, and wherein the human subject developed anoccurrence of a persistent and intolerable Grade 2 or Grade 3nonhematologic toxicity or non-life-threatening Grade 4 laboratoryabnormality during treatment with the prior dosage regimen; or a dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of 4 mg every other day, wherein the body weight ofthe human subject is equal to or more than 60 kg, wherein the humansubject was previously treated with a prior dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg/day, and wherein the human subject developed an occurrence of apersistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity ornon-life-threatening Grade 4 laboratory abnormality during treatmentwith the prior dosage regimen. 37.-41. (canceled)
 42. The method ofclaim 32, wherein the Grade 3 nonhematologic toxicity is selected fromthe group consisting of Grade 3 hypertension, Grade 3 diarrhea, Grade 3arthralgia, Grade 3 myalgia, Grade 3 decreased appetite, Grade 3fatigue, Grade 3 decreased weight, Grade 3 dysphonia, Grade 3 nausea,Grade 3 abdominal pain, Grade 3 QT/QTc interval prolongation, Grade 3hypothyroidism, Grade 3 vomiting, Grade 3 constipation, Grade 3 rash,and Grade 3 palmar-plantar erythrodysesthesia.
 43. The method of claim34, wherein the Grade 2 or Grade 3 nonhematologic toxicity is selectedfrom the group consisting of Grade 3 hypertension, Grade 2 hypertension,Grade 3 diarrhea, Grade 2 diarrhea, Grade 3 decreased appetite, Grade 2decreased appetite, Grade 3 arthralgia, Grade 2 arthralgia, Grade 3myalgia, Grade 2 myalgia, Grade 3 fatigue, Grade 2 fatigue, Grade 3decreased weight, Grade 2 decreased weight, Grade 2 alopecia, Grade 3dysphonia, Grade 2 dysphonia, Grade 3 nausea, Grade 2 nausea, Grade 3abdominal pain, Grade 2 abdominal pain, Grade 3 QT/QTc intervalprolongation, Grade 2 QT/QTc interval prolongation, Grade 3hypothyroidism, Grade 2 hypothyroidism, Grade 3 vomiting, Grade 2vomiting, Grade 3 constipation, Grade 2 constipation, Grade 3 rash,Grade 2 rash, Grade 3 palmar-plantar erythrodysesthesia, and Grade 2palmar-plantar erythrodysesthesia.
 44. The method of claim 36, whereinthe Grade 4 laboratory abnormality is selected from the group consistingof Grade 4 increase in aspartate aminotransferase, Grade 4 increase inalanine aminotransferase, Grade 4 increase in alkaline phosphatase,Grade 4 hypokalemia, Grade 4 hyponatremia, Grade 4 hypoglycemia, Grade 4increase in blood bilirubin, and Grade 4 increase in gamma glutamyltransferase. 45.-46. (canceled)
 47. The method of claim 1, which is amethod of treating unresectable hepatocellular carcinoma, the methodcomprising administering to a human subject that has an unresectablehepatocellular carcinoma a first dosage regimen comprising lenvatinib ora pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 8 mg/day if the body weight of the human subject is less than 60kg, (I) wherein the human subject develops an occurrence of a firstpersistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade4 laboratory abnormality during treatment with the first dosage regimen,and the method further comprises: (a) terminating administration of thefirst dosage regimen after the occurrence of the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the first persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and administering to the human subject a seconddosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of (i) 8 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 4 mg/day if the bodyweight of the human subject is less than 60 kg, wherein the humansubject develops an occurrence of a second persistent and intolerableGrade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormalityduring treatment with the second dosage regimen; (b) terminatingadministration of the second dosage regimen after the occurrence of thesecond persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality until the second persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality is resolved to Grade 0-1 or baseline, and administering tothe human subject a third dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg every other day if the body weight of the human subject isless than 60 kg, wherein the human subject develops an occurrence of athird persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality during treatment with the third dosageregimen; and (c) terminating administration of the third dosage regimenafter the occurrence of the third persistent and intolerable Grade 2 orGrade 3 adverse reaction or Grade 4 laboratory abnormality until thethird persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality is resolved to Grade 0-1 or baseline,and, if the body weight of the human subject is equal to or more than 60kg, administering to the human subject a fourth dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of 4 mg every other day; or (II) wherein the human subject developsan occurrence of a Grade 4 adverse reaction excluding Grade 4 laboratoryabnormality during treatment with the first, second, third, or fourthdosage regimen, and the method further comprises terminatingadministration of the dosage regimen after the occurrence of the Grade 4adverse reaction excluding Grade 4 laboratory abnormality; provided thatGrade 3 hypertension, Grade 4 hypertension, Grade 3 cardiac dysfunction,Grade 4 cardiac dysfunction, any grade arterial thromboembolic event,Grade 3 hepatotoxicity, Grade 4 hepatotoxicity, 2 g or greaterproteinuria in 24 hours, Grade 3 renal failure or impairment, Grade 4renal failure or impairment, any Grade gastrointestinal perforation,Grade 3 fistula, Grade 4 fistula, a greater than 500 ms QT/QTc intervalprolongation, a greater than 60 ms increase from baseline QT/QTcinterval prolongation, and any Grade reversible posteriorleukoencephalopathy syndrome are excluded from the persistent andintolerable Grade 2, Grade 3, or Grade 4 adverse reaction or Grade 4laboratory abnormality.
 48. (canceled)
 49. The method of claim 1, whichis a method of treating unresectable hepatocellular carcinoma, themethod comprising administering to a human subject that has anunresectable hepatocellular carcinoma a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 12 mg/day if the body weight of the human subject is equal to ormore than 60 kg or (ii) 8 mg/day if the body weight of the human subjectis less than 60 kg, (I) wherein the human subject develops an occurrenceof a first persistent and intolerable Grade 2 or Grade 3 adversereaction or Grade 4 laboratory abnormality during treatment with thefirst dosage regimen, and the method further comprises terminatingadministration of the first dosage regimen after the occurrence of thefirst persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality until the first persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality is resolved to Grade 0-1 or baseline, and administering tothe human subject a second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg; or (II) wherein the human subject develops an occurrence of a Grade4 adverse reaction excluding Grade 4 laboratory abnormality duringtreatment with the first dosage regimen, and the method furthercomprises terminating administration of the dosage regimen after theoccurrence of the Grade 4 adverse reaction excluding Grade 4 laboratoryabnormality; provided that Grade 3 hypertension, Grade 4 hypertension,Grade 3 cardiac dysfunction, Grade 4 cardiac dysfunction, any gradearterial thromboembolic event, Grade 3 hepatotoxicity, Grade 4hepatotoxicity, 2 g or greater proteinuria in 24 hours, Grade 3 renalfailure or impairment, Grade 4 renal failure or impairment, any Gradegastrointestinal perforation, Grade 3 fistula, Grade 4 fistula, agreater than 500 ms QT/QTc interval prolongation, a greater than 60 msincrease from baseline QT/QTc interval prolongation, and any Gradereversible posterior leukoencephalopathy syndrome are excluded from thepersistent and intolerable Grade 2, Grade 3 or Grade 4 adverse reactionor Grade 4 laboratory abnormality.
 50. (canceled)
 51. The method ofclaim 1, which is a method of treating unresectable hepatocellularcarcinoma, the method comprising administering to a human subject thathas an unresectable hepatocellular carcinoma a first dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 12 mg/day if the body weight of the human subject is equalto or more than 60 kg or (ii) 8 mg/day if the body weight of the humansubject is less than 60 kg, (I) wherein the human subject develops anoccurrence of a first persistent and intolerable Grade 2 or Grade 3adverse reaction or Grade 4 laboratory abnormality during treatment withthe first dosage regimen, and the method further comprises: (a)terminating administration of the first dosage regimen after theoccurrence of the first persistent and intolerable Grade 2 or Grade 3adverse reaction or Grade 4 laboratory abnormality until the firstpersistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade4 laboratory abnormality is resolved to Grade 0-1 or baseline, andadministering to the human subject a second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 8 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg/day if the body weight of the human subject isless than 60 kg, wherein the human subject develops an occurrence of asecond persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality during treatment with the second dosageregimen; (b) terminating administration of the second dosage regimenafter the occurrence of the second persistent and intolerable Grade 2 orGrade 3 adverse reaction or Grade 4 laboratory abnormality until thesecond persistent and intolerable Grade 2 or Grade 3 adverse reaction orGrade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, andadministering to the human subject a third dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 4 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg every other day if the body weight of the humansubject is less than 60 kg, wherein the human subject develops anoccurrence of a third persistent and intolerable Grade 2 or Grade 3adverse reaction or Grade 4 laboratory abnormality during treatment withthe third dosage regimen; and (c) terminating administration of thethird dosage regimen after the occurrence of the third persistent andintolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratoryabnormality until the third persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality is resolved toGrade 0-1 or baseline, and, if the body weight of the human subject isequal to or more than 60 kg, administering to the human subject a fourthdosage regimen comprising lenvatinib or a pharmaceutically acceptablesalt thereof at a dose of 4 mg every other day; or (II) wherein thehuman subject develops an occurrence of a Grade 4 adverse reactionexcluding Grade 4 laboratory abnormality during treatment with thefirst, second, third, or fourth dosage regimen, and the method furthercomprises terminating administration of the dosage regimen after theoccurrence of the Grade 4 adverse reaction excluding Grade 4 laboratoryabnormality; provided that hypertension, cardiac dysfunction, arterialthromboembolic event, hepatotoxicity, proteinuria, renal failure orimpairment, gastrointestinal perforation, fistula, QT/QTc intervalprolongation, and reversible posterior leukoencephalopathy syndrome areexcluded from the persistent and intolerable Grade 2, Grade 3, or Grade4 adverse reaction or Grade 4 laboratory abnormality.
 52. (canceled) 53.The method of claim 1, which is a method of treating unresectablehepatocellular carcinoma, the method comprising administering to a humansubject that has an unresectable hepatocellular carcinoma a first dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, (I) wherein the humansubject develops an occurrence of a first persistent and intolerableGrade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormalityduring treatment with the first dosage regimen, and the method furthercomprises terminating administration of the first dosage regimen afterthe occurrence of the first persistent and intolerable Grade 2 or Grade3 adverse reaction or Grade 4 laboratory abnormality until the firstpersistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade4 laboratory abnormality is resolved to Grade 0-1 or baseline, andadministering to the human subject a second dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 8 mg/day if the body weight of the human subject is equal to or morethan 60 kg or (ii) 4 mg/day if the body weight of the human subject isless than 60 kg; or (II) wherein the human subject develops anoccurrence of a Grade 4 adverse reaction excluding Grade 4 laboratoryabnormality during treatment with the first dosage regimen, and themethod further comprises terminating administration of the dosageregimen after the occurrence of the Grade 4 adverse reaction excludingGrade 4 laboratory abnormality; provided that hypertension, cardiacdysfunction, arterial thromboembolic event, hepatotoxicity, proteinuria,renal failure or impairment, gastrointestinal perforation, fistula,QT/QTc interval prolongation, and reversible posteriorleukoencephalopathy syndrome are excluded from the persistent andintolerable Grade 2, Grade 3, or Grade 4 adverse reaction or Grade 4laboratory abnormality.
 54. (canceled)
 55. The method of claim 1, whichis a method of treating unresectable hepatocellular carcinoma, themethod comprising administering to a human subject that has anunresectable hepatocellular carcinoma a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 12 mg/day if the body weight of the human subject is equal to ormore than 60 kg or (ii) 8 mg/day if the body weight of the human subjectis less than 60 kg, wherein the human subject develops an occurrence ofa Grade 3 hypertension during treatment with the first dosage regimen,and the method further comprises terminating administration of the firstdosage regimen after the occurrence of the Grade 3 hypertension untilthe Grade 3 hypertension is controlled at less than or equal to Grade 2,and administering to the human subject the second dosage regimencomprising lenvatinib or a pharmaceutically acceptable salt thereof at adose of (i) 8 mg/day if the body weight of the human subject is equal toor more than 60 kg or (ii) 4 mg/day if the body weight of the humansubject is less than 60 kg.
 56. (canceled)
 57. The method of claim 1,which is a method of treating unresectable hepatocellular carcinoma, themethod comprising administering to a human subject that has anunresectable hepatocellular carcinoma a first dosage regimen comprisinglenvatinib or a pharmaceutically acceptable salt thereof at a dose of(i) 12 mg/day if the body weight of the human subject is equal to ormore than 60 kg or (ii) 8 mg/day if the body weight of the human subjectis less than 60 kg, wherein the human subject develops an occurrence ofa 2 g or greater proteinuria in 24 hours during treatment with the firstdosage regimen, and the method further comprises terminatingadministration of the dosage regimen after the occurrence of the 2 g orgreater proteinuria in 24 hours until the proteinuria is less than orequal to 2 g of proteinuria in 24 hours and, administering to the humansubject the second dosage regimen comprising lenvatinib or apharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg, provided that the human subject develops an occurrence of anephrotic syndrome during treatment with the first dosage regimen, andthe method further comprises terminating administration of the dosageregimen after the occurrence of the nephrotic syndrome.
 58. (canceled)59. The method of claim 1, which is a method of treating unresectablehepatocellular carcinoma, the method comprising administering to a humansubject that has an unresectable hepatocellular carcinoma a first dosageregimen comprising lenvatinib or a pharmaceutically acceptable saltthereof at a dose of (i) 12 mg/day if the body weight of the humansubject is equal to or more than 60 kg or (ii) 8 mg/day if the bodyweight of the human subject is less than 60 kg, wherein the humansubject develops an occurrence of a greater than 500 ms QT/QTc intervalprolongation or a greater than 60 ms increase from baseline QT/QTcinterval prolongation during treatment with the first dosage regimen,and the method further comprises terminating administration of thedosage regimen after the occurrence of the greater than 500 ms QT/QTcinterval prolongation or a greater than 60 ms increase from baselineQT/QTc interval prolongation until the QT/QTc interval prolongationimproves to less than or equal to 480 ms or baseline and, administeringto the human subject the second dosage regimen comprising lenvatinib ora pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day ifthe body weight of the human subject is equal to or more than 60 kg or(ii) 4 mg/day if the body weight of the human subject is less than 60kg. 60.-82. (canceled)
 83. The method of claim 1, wherein lenvatinib orthe pharmaceutically acceptable salt thereof is formulated as a capsule.84. The method of claim 1, wherein lenvatinib or the pharmaceuticallyacceptable salt thereof is administered to the human subject orally. 85.The method of claim 1, wherein lenvatinib or a pharmaceuticallyacceptable salt thereof is lenvatinib mesylate.